When we get better at using these technologies, we can find more oncogenic fusions and companies will be smart enough to find the agents that target them.
|
|
The Roche compound is designed to tackle several oncogenic mutations and last month, it unveiled data here on entrectinib pushing back tumors in 77 percent of lung cancer patients with a mutation called ROS1.
|
|
Oncogenic osteomalacia also known as oncogenic hypophosphatemic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia. It may be caused by a phosphaturic mesenchymal tumor.
|
|
The human papillomavirus 16 E5 protein, the least well-studied of the three known oncogenic HPV proteins, was reported in 2012 to be a viroporin. This was the first known example of an oncogenic viroporin.
|
|
Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas.
|
|
This gene has been found to be involved in maintenance of oncogenic transformation.
|
|
Many biological endpoints have been studied including oncogenic transformation, apoptosis, mutations, and chromosomal aberrations.
|
|
The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes & development 24, 2383-2388.
|
|
Genomic instability through various means such as DNA damage and epigenetic modifications appear to be the basic causes of sporadic (non-familial) cancer. While infections have many effects, infectious organisms that increase the risk of cancer are frequently a source of DNA damage or genomic instability, as discussed below for oncogenic viruses and an oncogenic bacterium.
|
|
Excess DNA damages, when present in replicating cells, can cause an increase in oncogenic mutations through error-prone translesion synthesis during replication.
|
|
They only become tumorigenic when infected into certain rodent species, such as Syrian hamsters. Some viruses are tumorigenic when they infect a cell and persist as circular episomes or plasmids, replicating separately from host cell DNA (Epstein–Barr virus and Kaposi's sarcoma-associated herpesvirus). Other viruses are only carcinogenic when they integrate into the host cell genome as part of a biological accident, such as polyomaviruses and papillomaviruses. A direct oncogenic viral mechanism involves either insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes (proto-oncogenes) in the genome.
|
|
In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
|
|
To recap, the oncogenic PRL-2 is responsible for regulating tumor growth, setting intracellular levels of magnesium by joining with the CNNM3 magnesium transporter.
|
|
Meanwhile, in colon and liver cancers, SMYD3-mediated methylation of H3 promotes RNAP II recruitment and the associated transcription factors from proto-oncogenic regions.
|
|
In Western developed countries, human papillomavirus (HPV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most frequently encountered oncogenic DNA viruses.
|
|
While some fusion transcripts occur via trans- splicing in normal human cells, trans-splicing can also be the mechanism behind certain oncogenic fusion transcripts.
|
|
MassARRAY spectrometry is more sensitive than PreTect HPV-Proofer and Consensus PCR for type-specific detection of high-risk oncogenic human papillomavirus genotypes in cervical cancer.
|
|
It is possible that controlled miR-675 release from H19 may enable a rapid inhibition of cell proliferation in response to cellular stress or oncogenic signals.
|
|
A number of substrates have been discovered for these enzymes. Deregulation, including constitutive activation or over expression, may contribute to the progression of cellular transformation and oncogenic activity.
|
|
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.
|
|
Cancer cells can manipulate cell signalling by producing excess levels of ROS, thereby constitutively activating pathways to promote their cellular growth and proliferation. Implicated pathways include NF-κB, PI3K, HIFs and MAPKs. In humans, mitochondrial ROS is required alongside those released in the oxidative burst for mitogenic pathway stimulation in oncogenic KRAS cells. However, in oncogenic Kras mice fibroblasts, NADPH oxidase inhibitors have been shown to be sufficient to block these growth factor pathways.
|
|
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.
|
|
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.
|
|
Obesity affects the liver through Non-alcoholic fatty liver disease which can cause steatohepatitis which in turn, due to the inflammation caused by the hepatitis, can cause oncogenic changes in hepatocytes.
|
|
Recently, it has been shown that trabectedin blocks DNA binding of the oncogenic transcription factor FUS-CHOP and reverses the transcriptional program in myxoid liposarcoma. By reversing the genetic program created by this transcription factor, trabectedin promotes differentiation and reverses the oncogenic phenotype in these cells. Other than transcriptional interference, the mechanism of action of trabectedin is complex and not completely understood. The compound is known to bind and alkylate DNA at the N2 position of guanine.
|
|
The first event leading to colon cancer is in 80 to 90% of cases a constitutive activation of the Wnt/ß-catenin oncogenic pathway induced by mutations in the APC (Adenomatous polyposis coli) coding gene or the ß-catenin coding gene. Mutations induction into normal intestinal stem cells is sufficient to trigger tumorigenesis. GAST gene which encodes hPG80 is activated by the Wnt oncogenic pathway. It is a downstream target of the ß-catenin/Tcf-4 signaling pathway.
|
|
Thus oncogenic JSRV has borrowed features of both pH-dependent and pH-independent viruses for entry which involves both the receptor binding and a low pH for fusion transformation of host cells.
|
|
Not all retroviral proteins are oncogenic.Definition: retroviridae proteins, oncogenic from Online Medical Dictionary The phrase was introduced as a MeSH term in 1990, under which over 6000 primary scientific publications are indexed.
|
|
Although retroviruses have different subfamilies, they have three basic groups. The oncoretroviruses (oncogenic retroviruses), the lentiviruses (slow retroviruses) and the spumaviruses (foamy viruses).{Miller, A. D. (2006). Retroviral Vectors in Gene Therapy.
|
|
Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer.
|
|
Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. The latter is common in lymphomas, where oncogenes are juxtaposed to the promoters of the immunoglobulin genes. Oncogenic fusion transcripts may also be caused by trans-splicing or read- through events. Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created.
|
|
DCN1-like protein 1 is a protein that in humans is encoded by the DCUN1D1 gene. DCUN1D1 is amplified in several cancer types, including squamous cell cancers, and may act as an oncogenic driver in cancer cells.
|
|
The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or with mutations of the actual DNA code for the gene itself.
|
|
301x301px Different molecular mechanisms are involved in PRCC development, which further result in distinct histologic features and clinical outcomes. Type 1 PRCC is caused by a genetic mutation or a gain in chromosome 7 where the MET gene is positioned, resulting in the promotion of oncogenic pathways in renal epithelial cells. Typically, the MET gene is upregulated for renal tissue repair and regeneration by encoding the receptor tyrosine kinase c-MET of hepatocyte growth factor. However, activation of the oncogenic pathway in the MET gene will manifest invasion, anti-apoptosis, angiogenesis, and metastasis.
|
|
Recently, Brpf1 was reported to play the tumor suppressor or oncogenic role in several malignant tumors, including leukemia, medulloblastoma and endometrial stromal sarcoma. Brpf1 was considered a tumor suppressor gene because mutations in cancer cells appear to diminish the function of Brpf1 However, oncogenic role of Brpf1 is also possible in cancer. For example, Brpf1 can form a stable complex with Moz- Tif2, which could lead to the development of human acute myeloid leukemia (AML). There is another Brpf1 related complex Brpf1–Ing5–Eaf6, which also plays a direct role in cancer.
|
|
The oncogenic receptor ECGFvIII, which is located in a specific type of aggressive glioma tumor, can be transferred to a non-aggressive population of tumor cells via microvesicles. After the oncogenic protein is transferred, the recipient cells become transformed and show characteristic changes in the expression levels of target genes. It is possible that transfer of other mutant oncogenes, such as HER2, may be a general mechanism by which malignant cells cause cancer growth at distant sites. microvesicles from non-cancer cells can signal to cancer cells to become more aggressive.
|
|
Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well- known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia.
|
|
125(Pt 13):3185-94.Elias MC, Pronovost SM, Cahill KJ, Beckerle MC, Kadrmas JL. (2012) A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted. J Cell Sci. 125(Pt 13):3185-94.[A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma.Sankar S, Tanner JM, Bell R, Chaturvedi A, Randall RL, Beckerle MC, Lessnick SL (2013). A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma. Mol Cell Biol, 33(22), 4448-60.
|
|
McDonagh, CF (2012) Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3. Molecular Cancer Therapeutics Membrane computing is the task of modelling specifically a cell membrane.
|
|
Epstein-Barr virus, like other oncogenic viruses, decreases the expression of TLR9 in B cells, diminishing production of TNF and IL-6. EBV has been reported to alter expression of TLR9 at the transcription, translation, and protein level.
|
|
Pages: 2, 8-22, via direct download.Drexel University College of Medicine, Symposium to Address Treatment and Prevention of Infectious Inflammatory and Oncogenic Disease. June 5, 2014.Miller School of Medicine at the University of Miami (2015), Translational Medicine Prize.
|
|
It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth.
|
|
He did his postgraduate studies in the research institutes of the academy in Moscow and Sukhumi. In 1977, Voevodin defended his Ph.D. thesis "Antigenic characterization of primate oncogenic viruses" at the Ivanovsky Virology Institute, Moscow. His mentor was Prof. Boris Lapin ().
|
|
Like other CML cells lines (e.g., K562) KBM-7 cells are positive for the Philadelphia chromosome harboring the BCR-ABL oncogenic fusion. KBM-7 cells have been reprogrammed to yield the HAP1 cell line which is also monosomic for chromosome 8.
|
|
The role that microRNAs play in cancer development and metastasis is under much scientific investigation and it is yet to be demonstrated whether microRNA mimics or antagomirs may serve as standard clinical treatments to suppress EMT or oncogenic microRNAs in cancers.
|
|
Midostaurin was found to be active against oncogenic CD135 (FMS- like tyrosine kinase 3 receptor, FLT3), in preclinical studies. Clinical trials have primarily focused on relapsed/refractory AML and MDS and have included single agent and combination agent studies. After successful Phase II clinical trials, midostaurin was found to prolong survival of FLT3-mutated AML patients when combined with conventional induction and consolidation therapies in a randomized Phase III clinical trial. On April 28, 2017, midostaurin was approved by the FDA for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.
|
|
Metastasis is a major cause of cancer deaths, and strategies to prevent or halt invasion are lacking. One study showed that autocrine PDGFR signaling plays an essential role in epithelial-mesenchymal transition (EMT) maintenance in vitro, which is known to correlate well with metastasis in vivo. The authors showed that the metastatic potential of oncogenic mammary epithelial cells required an autocrine PDGF/PDGFR signaling loop, and that cooperation of autocrine PDGFR signaling with oncogenic was required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways.
|
|
Fischbach earned his A.B. in Biochemical Sciences from Harvard College in 2003. During that time (2000-2003), he worked in Jeffrey Settleman’s lab at the Massachusetts General Hospital Cancer Center on the biochemistry of oncogenic mutants of the small GTPase Ras.Fischbach MA, Settleman J. Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. Cancer Res. 2003 Jul 15;63(14):4089-94. . In 2007, he earned his Ph.D. in Chemistry and Chemical Biology from Harvard University, working in Christopher T. Walsh’s laboratory at Harvard Medical School on iron acquisition in bacterial pathogens and the biochemistry of natural product biosynthesis.
|
|
EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member (e.g. ERG for FLI1).
|
|
IRS-1 dominant-negative mutant functions as tumor suppressor, whereas ectopic IRS-1 stimulates oncogenic transformation. IRS-1 is upregulated in colorectal cancers (CRC) with elevated levels of β-catenin, c-MYC, InsRβ and IGF1R. IRS-1 promotes CRC metastasis to the liver.
|
|
Such oncogenic pathways as the transformation growth factor (TGF)-beta signaling pathway stimulate cells to proliferate. In glioblastomas the overactivity of this pathway is associated with aggressive forms of tumor growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.
|
|
These studies suggest that the metabolites of cyclooxygenase, 5-lipoxygenase, and 12-lipoxygenase, i.e. 12-HHT, LTB4, and 12-HTE, respectively, may act through BLT2 receptors to contribute to the growth and spread of cancers initiated and/or oncogenic Ras and possibly other oncogenes.
|
|
Epstein-Barr virus encoded latent infection membrane protein-1 (LMP1) can interact with this and several other members of the TRAF family, which may be essential for the oncogenic effects of LMP1. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported.
|
|
The carcinoma can metastasize to the lungs, and less frequently in liver, bone, or other sites. SCC of the vagina is associated with a high rate of infection with oncogenic strains of human papillomavirus (HPV) and has many risk factors in common with cervical cancer.
|
|
In 1907, Loeb published a study which showed that breast carcinoma in mice could be hereditary, as it is now known to be in some human cases.Kenemans P, Verstraeten RA, Verheijen RH. Oncogenic pathways in hereditary and sporadic breast cancer. Maturitas 2008; 61: 141-150.
|
|
In mammals ILK lacks catalytic activity but supports scaffolding protein functions for focal adhesions. In plants, ILKs signal complexes to focal adhesion sites. ILKs of plants contain multiple ILK genes. Unlike animals that contain few ILK genes ILKs have been found to possess oncogenic properties.
|
|
The protein is nuclear in the M and G1 phases of the cell cycle and moves to the cytoplasm during S and G2. CDC25B has oncogenic properties, although its role in tumor formation has not been determined. Multiple transcript variants for this gene exist.
|
|
Somatic mutations in U2AF1 have been found in a range of human cancers, with a distinctive pattern of these mutations at the zinc fingers implicating a functional role under selection. In lung cancers, these mutations affect alternative splicing of several transcripts, including oncogenic ROS1 fusions.
|
|
Interestingly, even after oncogenic activation of a tissue, several researchers have identified a senescent phenotype. Researchers have identified a senescent phenotype in benign lesions of the skin carrying oncogenic mutations in neurofibroma patients with a defect that specifically causes an increase in Ras. This finding has been highly reproducible in benign prostate lesions, in melanocytic lesions of UV-irradiated HGF/SF-transgenic mice, in lymphocytes and in the mammary gland from N-Ras transgenic mice, and in hyperplasias of the pituitary gland of mice with deregulated E2F activity. The key to these findings is that genetic manipulations that abrogated the senescence response led to full-blown malignancy in those carcinomas.
|
|
A tumor suppressor role of STAT3 has also been reported. In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown. Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.
|
|
Moreover, the acquisition of oncogenic H-RasG12V by NK- and T lymphocytes had important biological functions in the adopting lymphocytes: the transferred H-RasG12V induced ERK phosphorylation, increased interferon-γ and tumor necrosis factor-α secretion, enhanced lymphocyte proliferation, and augmented NK-mediated target cell killing.
|
|
Recent findings indicate that the keratinizing squamous epithelium of the middle ear could be subjected to human papillomavirus infection. Indeed, DNA belonging to oncogenic HPV16 has been detected in Cholesteatoma tissues, thereby underling that keratinizing squamous epithelia could potentially be a target tissue for HPV infection.
|
|
Piebaldism is a kind of neurocristopathy, involving defects of various neural crest cell lineages that include melanocytes, but also involving many other tissues derived from the neural crest. Oncogenic factors, including mistranscription, are hypothesized to be related to the degree of phenotypic variation among affected individuals.
|
|
The glutamate residue of the mutant therefore functions to activate BRAF by inhibiting the interaction of the BRAF's glycine rich loop and activation segment, which would ordinarily be inhibitory. The loss of inhibition of BRAF leads to an increase in its basal activity and hence is oncogenic.
|
|
In subsequent investigations, about 25% of studied bone cancers displayed evidence of chromothripsis. Chromothripsis has been linked to the generation of oncogenic fusions in supratentorial ependymoma, chondromyxoid fibroma, and Ewing sarcoma, the latter two being bone tumours. Chromothripsis has been seen in 2–3% of cancers across all subtypes.
|
|
SF2/ASF creates an oncogenic form of S6K1 to increase the prevalence of cap- dependent translation. SF2/ASF can also interact with polyribosomes to directly influence translation of mRNA into protein by recruiting component of the mTOR pathway. SF2/ASF increases the phosphorylation of rpS6 and eIF4B by S6K1.
|
|
This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.
|
|
The protein encoded by this gene has ubiquitin-protein ligase activity. This protein binds with p53 and promotes the ubiquitin-mediated proteosomal degradation of p53. This gene is oncogenic because loss of p53 function contributes directly to malignant tumor development. Transcription of this gene is regulated by p53.
|
|
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors. Family of neurotrophin receptors including NTRK3 have been shown to induce a variety of pleiotorpic response in malignant cells, including enhanced tumor cell invasiveness and chemotoxis. Increased NTRK3 expression has been demonstrated in neuroblastoma, in medulloblastoma, and in neuroectodermal brain tumors.
|
|
Recent findings indicate that the middle ear mucosa could be subjected to human papillomavirus infection. Indeed, DNAs belonging to oncogenic HPVs, i.e., HPV16 and HPV18, have been detected in normal middle ear specimens, thereby underling that the normal middle ear mucosa could potentially be a target tissue for HPV infection.
|
|
Constitutive phosphorylation of 4E-BP1 is commonly found in cancers and contributes to the sustrained translation of malignancy related transcripts, among which are c-Myc and Cyclin D. Knockdown of PIM2 by iRNA strongly reduced the accumulation of oncogenic proteins. As a result, PIM2 may be an attractive target for acute myeloid leukemia.
|
|
Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer. BCAM-AKT2 is a fusion gene that is specific and unique to high-grade serous ovarian cancer.Deciphering the Cancer Transcriptome. 2016 Oncogenic fusion genes may lead to a gene product with a new or different function from the two fusion partners.
|
|
Normal cells have apoptotic proteins that will respond to an overstimulation of mitogenic signaling pathways by triggering cell death or senescence. This generally prevents the onset of cancer from a single oncogenic mutation. In tumor cells, there is generally another mutation that inhibits apoptotic proteins as well, suppressing the hyperproliferation stress response.
|
|
Other agents that induce p53 dependent apoptosis are neurotoxins, proteasome inhibitors, microtubule poisons, and transcription inhibitors. PUMA apoptosis may also be induced independently of p53 activation by other stimuli, such as oncogenic stress growth factor and/or cytokine withdrawal and kinase inhibition, ER stress, altered redox status, ischemia, immune modulation, and infection.
|
|
In humans, there are 32 cytoplasmic protein tyrosine kinases (). The first non-receptor tyrosine kinase identified was the v-src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases. A chicken sarcoma virus was found to carry mutated versions of the normal cellular Src gene.
|
|
Its role as a master regulator of morphogenesis during human development makes it an ideal candidate for perturbation in malignant tissues. Specifically, Sox9 appears to induce invasiveness and therapy-resistance in prostate, colorectal, breast and other cancers, and therefore promotes lethal metastasis. Many of these oncogenic effects of Sox9 appear dose dependent.
|
|
This gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine protein kinase family. This kinase can activate both the ERK1/2 and p38 MAP kinases. This kinase was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB.
|
|
This enzyme participates in purine metabolism. The results of a recent study indicate that the ERK2 signaling activated by growth and oncogenic signals leads to PFAS phosphorylation at the T619 site. In addition, ERK2-mediated PFAS phosphorylation is required for cell and tumor growth. It is known as ADE6 in Saccharomyces cerevisiae (budding yeast) genetics.
|
|
An oncomir (also oncomiR) is a microRNA (miRNA) that is associated with cancer. MicroRNAs are short RNA molecules about 22 nucleotides in length. Essentially, miRNAs specifically target certain messenger RNAs (mRNAs) to prevent them from coding for a specific protein. The dysregulation of certain microRNAs (oncomirs) has been associated with specific cancer forming (oncogenic) events.
|
|
The first link between miRNA and the growth of cancer was reported in 2002 when researchers observed a down-regulation of miR-15a and miR-16-1 in B-cell chronic lymphocytic leukemia patients. The term is a portmanteau, derived from "oncogenic" + "miRNA", coined by Scott M. Hammond in a 2006 paper characterizing OncomiR-1.
|
|
In rats, the oncogenic SV40 large T antigen was used to establish a brain tumor model for primitive neuroectodermal tumor and medulloblastoma. The molecular mechanisms by which the virus reproduces and alters cell function were previously unknown, and research into SV40 vastly increased biologists' understanding of gene expression and the regulation of cell growth.
|
|
They found as well 2 distinctive chromosome 6p21.32-p21.2 and 6p11.2 amplification regions in the primary tumor which disappeared in the postchemotherapy specimen. Furthermore, the pretreatment biopsy showed strong expression of HMGA1 and HMGA2 proteins by immunohistochemistry and loss of expression after therapy thereby crediting the HMGA family of proteins for oncogenic expansion (9).
|
|
Curiously, DACH1 selectively bound to the delta domain of c-Jun, which was known to interact with an endogenous cellular repressor. DACH1 binds directly with a Forkhead-like DNA sequence to restrain oncogenic signals from a subset of FKHR proteins. Dach1 governs mRNA translation of an EMT signature and governs Snail1 transcription. Cell migration.
|
|
According to GWAS, C1orf94 was identified as an OncoORF (Oncogenic Open Reading frame). According to Colorectal cancer Atlas, C1orf94 is involved in protein-protein interactions with 50 nodes causing colorectal cancer like interactions with AKAP9 kinase anchor protein, which is the most dangerous one as it promotes colorectal cancer development by regulating Cdc42 interacting protein.
|
|
This addresses the issue in terms of modeling the amplification of HER2 in mice development. In the non-fused mouse, the mammary gland would revert to a near virgin, but with this addition the mammary gland maintained the developed function.Fry, EA; Taneka, P; Inoue, K. (2016). Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu.
|
|
Also in 2007, they were the first to produce human iPS cells. However, there are some difficulties to overcome. The first is the issue of the very low production rate of iPS cells, and the other is the fact that the 4 transcriptional factors are shown to be oncogenic. Nonetheless, this is a truly fundamental discovery.
|
|
Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 45(6): 592-601, 2013. .Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell.
|
|
The role of HPV in the remaining 25-30% is not yet clear. Oral sex is not risk free and results in a significant proportion of HPV-related head and neck cancer. Positive HPV16 status is associated with improved prognosis over HPV-negative OSCC. HPV can induce tumor by several mechanisms: # E6 and E7 oncogenic proteins.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer.
|
|
Greater than 90% of cases contain a clonal rearrangement of the T-cell receptor. Oncogenic potential is conferred by upregulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in cases of this lymphoma. The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5.
|
|
Nutrient utilization is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in rate-limiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in cancer is largely due to oncogenic activation of signal transduction pathways and transcription factors.
|
|
Downregulation of the PI3K/AKT survival pathway may result in the induction of cancer cell apoptosis and may decrease cancer cellular proliferation. IGF-1R, a receptor tyrosine kinase of the insulin receptor superfamily overexpressed by many cancer cell types, stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis; IGF-1R signaling has been implicated in tumorigenesis and metastasis.
|
|
A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway . This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.
|
|
Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar and more importantly, these cells can form tumors in nude mice due to PLK1 overexpression.
|
|
His encyclopedic textbook Oncogenic Viruses is still considered a leading source book for early work in the discovery of viruses causing cancer. Gross died of stomach cancer, a major cancer caused by infection with the Helicobacter pylori which he himself researched. A collection of his personal papers are held at the National Library of Medicine in Bethesda, Maryland.
|
|
Several kinds of viruses with oncogenic potential are suspected to play a role or cause breast cancer. Among the three most commonly studied are the human papilloma virus (HPV), mouse mammary tumour virus (MMTV) and the Epstein-Barr virus (EBV). A study published in 2011, reviewing 85 original molecular research investigations on the presence of one or more of these three viruses found that only seven of the studies convincingly demonstrated the presence of an oncogenic virus biomarker, while twenty-five of the studies were able to show the absence of the virus studied, and the remaining studies were excluded due to shortcomings. Thus, the data from these investigations do not justify a conclusion as to whether HPV, MMTV, or EBV play a causal role in human breast cancer development.
|
|
Many human oncogenic viruses have been identified. For instance, HHV-8 is linked to Kaposi's sarcoma, the Epstein–Barr virus to Burkitt's lymphoma, and HPV to cervical cancer. In fact, the World Health Organization estimated (2002) that 17.8% of human cancers were caused by infection. The typical methods whereby viruses initiate oncogenesis involve suppressing the host's immune system, causing inflammation, or altering genes.
|
|
The morphology of TGEV was mostly determined by electron microscopy techniques. The morphology is similar to myxovirus and oncogenic virus in that they have surface projections and an envelop. The viruses are mainly circular in shape with a diameter ranging from 100 to 150 nm including the surface projections. The projections were mainly petal-shaped attached by a very narrow stalk.
|
|
For example, many GAPs of the small G proteins have a conserved finger-like domain, usually an arginine finger, which changes the conformation of the GTP-bound G protein to orient the GTP for better nucleophilic attack by water.Scheffzek, K. et al. "The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants". Science. 277 (1997): 333–338.
|
|
Recently it has been discovered that small RNA can trigger specific gene silencing in human cells. The RNAi reaction enables a complete elimination of a specific protein which can potentially enable researchers to target pivotal structures within a cell to eliminate the cell altogether. RNAi silencing can also strongly inhibit proliferation of cells with genetic mutations that encourage oncogenic activation.
|
|
Moshe Yaniv, born in 1938 in Hadera, Israel, is a French-Israeli molecular biologist who has studied the structure and functions of oncogenic DNA viruses as well as the general mechanisms for regulating gene expression in higher organisms and their deregulation during tumor pathologies and development. He is a member of the French Academy of sciences and Professor Emeritus at the Institut Pasteur.
|
|
Beta-catenin is a transcriptional activator and oncoprotein involved in the development of several cancers. The protein encoded by this gene interacts directly with the C-terminal region of beta-catenin, inhibiting oncogenic beta-catenin-mediated transcriptional activation by competing with transcription factors for binding to beta-catenin. Two transcript variants encoding different isoforms have been found for this gene.
|
|
Oncogenic h-ras has been found to increase expression of ERCC1, resulting in enhanced DNA repair (see above). Inhibition of h-ras was found to increase cisplatin sensitivity in glioblastoma cells. Upregulated expression of Bcl-2 in leukemic cells (non-Hodgkin’s lymphoma) resulted in decreased levels of apoptosis in response to chemotherapeutic agents, as Bcl-2 is a pro-survival oncogene.
|
|
While the response to ALK inhibitors is often very encouraging in patients with ALK+ NSCLC and lasts for a relatively long time, most of them eventually develop resistance, either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways. Much research is being carried out on understanding the ways the cancer adapts and on how to reverse or delay resistance.
|
|
This discovery led to Merck to voluntarily withdraw its killed-virus polio vaccine.Levine, A.J. The Origins of Small DNA Tumor Viruses In: Foundations in Cancer Research, Academic Press, 1994 pp. 152-153. Theoretically speaking, it added to a growing body of evidence that the monkey, like the mouse, could harbor oncogenic (cancer causing) viruses that could affect other animal species.
|
|
In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Finally Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host.
|
|
Tumors form in nose and are contagious. ENTV targets the respiratory system in ovine, specifically the upper-airway epithelial cells. Oncogenesis occurs in the nasal turbinate cells A typical oncogenic virus will cause a mutation in a host cell, causing the transformation of host cells from a protooncogene into an oncogene. ENTV is unique among retroviruses because the envelope glycoprotein is an oncogene.
|
|
Ford completed her Ph.D. at the University of New South Wales in oncogenic viruses, particularly related to breast cancer. She also has completed a Graduate Certificate in University Learning & Teaching. She completed her first postdoctoral research appointment at the University of Toronto and her second position was at Lund University where she investigated MMTV sequences in breast tumour samples from women and men.
|
|
Indirubin exerts its effects on the human body by downregulating expression of genes. Genes PLK1 and PIN1, both oncogenic, have been shown to be affected by indirubin. Indirubin has, in vitro and in vivo, been shown to reduce expression of the CDC25B gene, which codes for production of CDC25B enzyme. CDC stands for cell-division-cycle, and is used in cellular reproduction.
|
|
ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and cell polarity. These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility.
|
|
Strains A through E are highly related and are believed to have evolved from the same ancestor. The subgroups evolved to utilize difference cellular receptors to gain entry into avian cells due to the host developing resistance to viral entry. Some antigenic variation can occur within subgroups, and all strains are oncogenic, but oncogenicity and the ability to replicate varies between subgroups.
|
|
This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous.
|
|
Since the acetylation of STAT3 is important for its oncogenic activity and the fact that the level of acetylated STAT3 is high in cancer cells, it is implied that targeting acetylated STAT3 for chemoprevention and chemotherapy is a promising strategy. This strategy is supported by treating resveratrol, an inhibitor of acetylation of STAT3, in cancer cell line reverses aberrant CpG island methylation.
|
|
High miR-708 expression levels are observed in lung cancers due to their oncogenic role in lung cancer tumour growth and progression. miR-708 overexpression results in increased cell proliferation, migration, and invasion, and has therefore been associated with a decreased survival rate in lung epithelial cancers. It directly downregulates the transmembrane protein 88 (TMEM88), a negative regulator of the Wnt signalling pathway.
|
|
CARM1 plays an important role in androgen receptors and may play a role in prostate cancer progression. CARM1 exerts both oncogenic and tumor-suppressive functions. In breast cancer, CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. In pancreatic cancer, CARM1 methylates and inhibits MDH1 by disrupting its dimerization, which represses mitochondria respiration and inhibits glutamine utilization.
|
|
The function of WDCP is currently not well- understood, but due to increased expression levels in the bone marrow and thymus, the protein could have possible relations to immune function and development. Its location in the nucleus, relation to the MRN complex, an abundance of phosphorylation sites, and associations with various cancers could indicate a role in cell growth regulation or a proto-oncogenic function.
|
|
MYB drives proliferation of ACC cells and regulates genes involved in cell cycle control, DNA replication and repair, and RNA processing. Thus, the MYB oncogene is a potential diagnostic and therapeutic target in ACC. ACC has a relatively quiet genome with few recurrent copy number alterations or point mutations, consistent with the view that MYB and MYBL1 are the main oncogenic drivers of the disease.
|
|
Ceritinib is a selective and potent inhibitor of anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key step in the development and function of nervous system tissue. However, chromosomal translocation and fusion give rise to an oncogenic form of ALK that has been implicated in progression of NSCLC. Ceritinib thus acts to inhibit this mutated enzyme and stop cell proliferation, ultimately halting cancer progression.
|
|
Rb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins. Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomavirus, bind and inactivate pRb, this can lead to cancer. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.
|
|
The homology is significant enough to imply an evolutionary relationship between E6 and the beta chain of the ATP synthase family; however, they do not have the same function or enzyme activity. The E2 protein overlaps with the E4 open reading frames in the other papillomaviruses. These differences in the E2 proteins likely determine how oncogenic a virus is. The noncoding region has a homologies with BPV1.
|
|
The EGFR signaling pathway is often exploited by many different types of cancers, and therefore is a common drug target. MM-151 can be used to block these oncogenic signaling pathways in order to prevent tumor growth and survival. In addition, the mixture of antibodies can bind multiple parts of the EGFR molecule, so the cancer cannot develop resistance by mutating one site at a time.
|
|
The discovery of Wnt signaling was influenced by research on oncogenic (cancer-causing) retroviruses. In 1982, Roel Nusse and Harold Varmus infected mice with mouse mammary tumor virus in order to mutate mouse genes to see which mutated genes could cause breast tumors. They identified a new mouse proto-oncogene that they named int1 (integration 1). Int1 is highly conserved across multiple species, including humans and Drosophila.
|
|
Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti- angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.
|
|
GPC2 has been suggested as a therapeutic target in neuroblastoma. GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. Immunotoxins and chimeric antigen receptor (CAR) T cells targeting GPC2 inhibit neuroblastoma growth in mouse models.
|
|
Research in Green's laboratory focuses on gene regulation, particularly on the regulation of gene transcription and of RNA splicing. The group also studies the effects of regulatory patterns on the behavior of cancer cells, using genome-wide RNA interference screens to identify genes involved in cell proliferation or apoptosis in the context of oncogenic mutations. In 2014, Green began studying the rare genetic disease Rett syndrome.
|
|
Herpesviruses have large genomes containing a wide array of genes. Although the first ORF in these gammaherpesviruses have oncogenic potential, other viral genes may also play a role in viral transformation. A striking feature of the four gammaherpesviruses is that they contain distinct ORFs involved in lymphocyte signaling events. At the left end of each viral genome are located ORFs encoding distinct transforming proteins.
|
|
Not all retinoblastoma cases are with RB1 inactivation. There are cases reported with only one RB1 mutation or even two functional RB1 alleles, which indicates other oncogenic lesions of retinoblastoma. Somatic amplification of the MYCN oncogene is responsible for some cases of nonhereditary, early-onset, aggressive, unilateral retinoblastoma. MYCN can act as a transcription factor and promotes proliferation by regulating the expression of cell cycle genes.
|
|
Meta-analyses of multiple genome-wide association studies has suggested an association of SNPs in the ETS1 locus with psoriasis in European populations. This is not surprising because Ets1 is a negative regulator of Th17 cells. Ets1 overexpression in stratified squamous epithelial cells causes pro-oncogenic changes, such as suspension of terminal differentiation, high secretion of matrix metalloproteases (Mmps), epidermal growth factor ligands, and inflammatory mediators.
|
|
Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved in cell differentiation. Additionally, succinate- promoted activation of HIF-1α generates a pseudo-hypoxic state that can promote tumorneogensis by transcriptional activation of genes involved in proliferation, metabolism and angiogenesis. The other two oncometabolites, fumarate and 2-hydroxyglutarate have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.
|
|
The response of the INK4a/ARF/INK4b locus efficiently prevents cancers that could occur to the constant oncogenic mutations that occur in long-lived mammals. When the INK4a/ARF/INK4b locus was overexpressed, the mice demonstrated a 3-fold reduction in the incidence of spontaneous cancers. This evidence further indicated that the INK4a/ARF/INK4b locus in mice plays a role in tumor suppression.
|
|
EpCAM can be cleaved which lends the molecule oncogenic potential. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with the proteins FHL2, β-catenin, and Lef inside the nucleus. This complex then binds to DNA and promotes the transcription of various genes.
|
|
Hepatitis B virus down-regulates the expression of TLR9 in pDCs and B cells, destroying the production of IFNα and IL-6. However, just as in HPV, as the disease progresses TLR9 expression is up-regulated. HBV induces an oncogenic transformation, which leads to a hypoxic cellular environment. This environment causes the release of mitochondrial DNA, which has CpG regions that can bind to TLR9.
|
|
SRCCs are dedifferentiated adenocarcinomas that lose the capability for cell–cell interaction. Highly differentiated adenocarcinomas form SRCCs via a loss of adherens and tight junctions that typically separate MUC4, a mucin protein, and ErbB2, an oncogenic receptor. When MUC4 and ErbB2 are able to interact, they trigger an activation loop. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell–cell interactions are lost and signet carcinomas are formed.
|
|
GAB2 has been linked to the oncogenesis of many cancers including colon, gastric, breast, and ovarian cancer. Studies suggest that GAB2 is used to amplify the signal of many RTKs implicated in breast cancer development and progression. GAB2 has been particularly characterized for its role in leukemia. In chronic myelogenous leukemia (CML), GAB2 interacts with the Bcr-Abl complex and is instrumental in maintaining the oncogenic properties of the complex.
|
|
Promyelocytic leukemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.1–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. PML bodies are named after one of their major components, the promyelocytic leukemia protein (PML). They are often seen in the nucleus in association with Cajal bodies and cleavage bodies.
|
|
Loss-of-function mutations often affect tumor suppressor genes such as NF1, TP53 and CDKN2A. Other oncogenic alterations include fusions involving various kinases such as BRAF, RAF1, ALK, RET, ROS1, NTRK1., NTRK3 and MET BRAF, RAS, NF1 mutations and kinase fusions are remarkably mutually-exclusive, as they occur in different subsets of patients. Assessment of mutation status can therefore improve patient stratification and inform targeted therapy with specific inhibitors.
|
|
Bracken fern increases the oncogenic risk in humans. Epidemiological survey revealed that bracken fern consumption was positively correlated with esophageal cancer and with gastric cancer in many geographical areas of the world. In 1989, Natori and co-workers showed that ptaquiloside had clastogenic effect and caused chromosomal aberration in mammalian cells. In 2003, Santos group reported significantly increased levels of chromosomal abnormalities, such as chromatid breaks in cultured peripheral lymphocytes.
|
|
Back in France in 1972, he joined the Institut Pasteur as team leader and then as head of the Oncogenic Virus Unit (1975). In 1966, he was appointed Head of Research at the CNRS, in 1972 he became Director of Research and Professor at the Institut Pasteur in 1986. During his career at the Institut Pasteur, he headed the Molecular Biology Department (1986-1988) and the Biotechnology Department (1992-1994).
|
|
ERK3/MAPK6 interacts with and phosphorylated steroid receptor coactivator 3 (SRC-3) This coreceptor is an oncogenic protein which when overexpressed at serine 857 leads to cancer. After the phosphorylation of SRC-3 results in the upregulation of MMP activity ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity.
|
|
Epstein–Barr virus stable intronic-sequence RNAs (ebv-sisRNAs) are a class of non-coding RNAs generated by repeat introns in the Epstein–Barr virus. After EBERs 1 and 2, ebv-sisRNA-1 is the third most abundant EBV RNA generated during a highly oncogenic form of virus latency (latency III). Conservation of ebv-sisRNA sequence and secondary structure between EBV and other herpesviruses suggest shared functions in latent infection.
|
|
Because many viruses integrate their own genomes into the genomes of their host cells in order to replicate, mutagenesis caused by viral infections is a fairly common occurrence. Not all integrating viruses cause insertional mutagenesis, however. Some DNA insertions will lead to no noticeable mutation. In recent gene therapy trials, the lentiviral vectors used to insert therapeutic DNA showed no tendency to disrupt gene function or promote oncogenic development.
|
|
Binding the PDZ domain of this phosphatase results in a loss of enzyme activity, which leads to apoptosis. The normal regulation of this enzyme prevents cells from prematurely going through apoptosis. When the regulation of the PTPN4 enzyme is lost, there is increased oncogenic activity as the cells are able to proliferate. PDZ domains also have a regulatory role in mechanosensory signaling in proprioceptors and vestibular and auditory hair cells.
|
|
TRPM family of ion channels are particularly associated with prostate cancer where TRPM2 (and its long noncoding RNA TRPM2-AS), TRPM4, and TRPM8 are overexpressed in prostate cancer associated with more aggressive outcomes. TRPM3 has been shown to promote growth and autophagy in clear cell renal cell carcinoma, TRPM4 is overexpressed in diffuse large B-cell lymphoma associated with poorer survival, while TRPM5 has oncogenic properties in melanoma.
|
|
SV40 was first identified by Ben Sweet and Maurice Hilleman in 1960 when they found that between 10-30% of polio vaccines in the USA were contaminated with SV40. In 1962, Bernice Eddy described the SV40 oncogenic function inducing sarcoma and ependymomas in hamsters inoculated with monkeys cells infected with SV40. The complete viral genome was sequenced by Fiers and his team at the University of Ghent (Belgium) in 1978.
|
|
SP initiates expression of almost all known immunological chemical messengers (cytokines). Also, most of the cytokines, in turn, induce SP and the NK1 receptor. SP is particularly excitatory to cell growth and multiplication, via usual, as well as oncogenic driver. SP is a trigger for nausea and emesis, Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints.
|
|
In humans, the main function of ROCK1 is actomyosin contractility. As mentioned before, this contributes to many proximal progresses such as regulation of morphology, motility, and cell–cell and cell–matrix adhesion. In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Given this diverse range of functions, it is not surprising that ROCK1 has been implicated in numerous aspects of cancer.
|
|
It was found that RASSF1A was silenced in cancer cells when the promoter region was hypermethylated. It is speculated that cancer subtypes may develop due to the inverse relationship of RASSF1A and HPV. RASSF1A promoter hypermethylation and oncogenic HPV were detected in ACs, but SCCs displayed a high level of HPV DNA and no RASSF1A promoter methylation. Another study used Hela cells to study the potential therapeutic effects of RASSF1A.
|
|
Researchers discovered the carcinogenic nature of ZNF703 in 2011 while conducting research on the classification and resistance of various oncogenes. Researchers attempted to discern factors associated with various cancer types through observation of the oncogenic mechanism on a molecular scale. The luminal B cancer pathway exhibited an amplification of 5 different genomic areas including the chromosome region 8p12. Amplification of region 8p12 occurred through transcriptional regulation of ZNF703.
|
|
RSV was discovered in 1911 by Peyton Rous, working at Rockefeller University in New York City, by injecting cell free extract of chicken tumour into healthy Plymouth Rock chickens. The extract was found to induce oncogenesis. The tumour was found to be composed of connective tissue (a sarcoma). Thus, RSV became known as the first oncogenic retrovirus that could be used to study the development of cancer molecularly.
|
|
WRAP53β is overexpressed in a variety of cancer cell lines of different origins and such overexpression promotes carcinogenic transformation indicating that this protein possesses oncogenic properties.Mahmoudi, S., Henriksson, S., Farnebo, L., Roberg, K. & Farnebo, M. WRAP53 promotes cancer cell survival and is a potential target for cancer therapy. Cell Death Dis 2, e114, doi:10.1038/cddis.2010.90 (2011). WRAP53β is overexpressed in primary nasopharyngeal carcinoma,Sun, C. K. et al.
|
|
HTLV-1 is also associated with adult T-cell leukemia/lymphoma and has been quite well studied in Japan. The time between infection and onset of cancer also varies geographically. It is believed to be about sixty years in Japan and less than forty years in the Caribbean. The cancer is thought to be due to the pro-oncogenic effect of viral RNA incorporated into host lymphocyte DNA.
|
|
Pescadillo homolog is a protein that in humans is encoded by the PES1 gene. This gene encodes a protein that is abnormally elevated in malignant tumors of astrocytic origin. It is a strongly conserved gene containing a BRCT domain that is essential for the activity of this gene product. The gene plays a crucial role in cell proliferation and may be necessary for oncogenic transformation and tumor progression.
|
|
This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and tyrosine kinase signaling and T-cell activation. Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2. Mutations that renders the Cbl protein dysfunctional due to the loss of its ligase/tumor suppressor function and maintenance of its positive signaling/oncogenic function have been shown to cause development of cancer.
|
|
HER2 is overexpressed in 20-30% of breast cancers and is commonly associated with poor prognosis. It is therefore an oncogene whose differently spliced variants have been shown to have different functions. Knocking down hnRNP H1 was shown to increase the amount of an oncogenic variant Δ16HER2. HER2 is an upstream regulator of cyclin D1 and p27, and its overexpression leads to the deregulation of the G1/S checkpoint.
|
|
Treatment options for aggressive metastatic cancer typically have a poor response rate to conventional treatments. Through this novel approach, analysis of oncogenic factors is undertaken to identify the unique molecular signatures of the individual's tumour. In most cancers, there are multiple pathways that are altered and lead to disease growth and progression. The pathways can vary from person to person, and even between different sites of disease in a single person.
|
|
Stepwise progression from normal tissue to precancerous lesion to invasive cancer The pathophysiology of precancerous lesions is thought to be similar to that of cancer, and varies depending on the disease site and type of lesion. It is thought that cancer is preceded by a clinically silent premalignant phase during which oncogenic genetic and epigenetic alterations accumulate. The duration of this premalignant phase can vary from cancer to cancer and from individual to individual.
|
|
In vivo footprinting experiments obtained on Cdc2 and B-myb promoters demonstrated E2F DNA binding site occupation during G0 and early G1, when E2F is in transcriptional repressive complexes with the pocket proteins. pRb is one of the targets of the oncogenic human papilloma virus protein E7, and human adenovirus protein E1A. By binding to pRB, they stop the regulation of E2F transcription factors and drive the cell cycle to enable virus genome replication.
|
|
Fibroblast growth factor 6 is a protein that in humans is encoded by the FGF6 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene displayed oncogenic transforming activity when transfected into mammalian cells.
|
|
It has been shown CDC6 shows proto-oncogenic activity. Cdc6 overexpression interferes with the expression of INK4/ARF tumor suppressor genes through a mechanism involving the epigenetic modification of chromatin at the INK4/ARF locus. In addition, CDC6 overexpression in primary cells may promote DNA hyperreplication and induce a senescence response similar to that caused by oncogene activation. These findings indicate that deregulation of CDC6 expression in human cells poses a serious risk of carcinogenesis.
|
|
HPV+OPC patients are therefore at less risk of developing other malignancies in the head and neck region, unlike other head and neck primary tumours that may have associated second neoplasms, that may occur at the same time (synchronous) or a distant time (metachronous), both within the head and neck region or more distantly. This suggests that the oncogenic alterations produced by the virus are spatially limited rather than related to a field defect.
|
|
Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
|
|
In Glioma, a type of brain cancer, TIGAR can be over-expressed where it has oncogenic-like effects. In this case, TIGAR acts to maintain energy levels for increased growth by increasing respiration (conferring altered metabolism), and also protects glioma cells against hypoxia-induced apoptosis by decreasing ROS (conferring evasion of apoptosis). TIGAR is also overexpressed in some breast cancers. In multiple myeloma, TIGAR expression is linked to the activity of MUC-1.
|
|
Fusion of two genes (BCR-ABL) to encode a recombinant oncogenic protein. A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves removing the stop codon from a cDNA sequence coding for the first protein, then appending the cDNA sequence of the second protein in frame through ligation or overlap extension PCR. That DNA sequence will then be expressed by a cell as a single protein.
|
|
Benabid developed stereotactic surgery methods for brain surgery in patients who had brain tumors or certain types of movement disorder. As part of the work, he and his team members created tissue banks using tissue from brain tumor biopsies. The tissue samples were used to characterize brain tumors by oncogenic mapping. Studies of genomics and proteomics have highlighted the factors involved in tumor progression and led to therapeutic advances such as anti-angiogenic factors.
|
|
AFPep ( _A_ lpha _F_ etoprotein _Pep_ tide) is an orally active cyclic peptide with molecular weight of 969 Daltons and is derived from the anti-oncogenic active site (residues 472-479) of alpha fetoprotein (AFP). Using the standard amino acid abbreviations, AFPep has the sequence cyclo-(EKTOVNOGN), where O is hydroxyproline. This peptide has been shown in experimental animal models to be efficacious in the prevention and treatment of ER+ breast cancer.
|
|
Overexpression of Skp2 is frequently observed in human cancer progression and metastasis, and evidence suggests that Skp2 plays a proto-oncogenic role both in vitro and in vivo. Skp2 overexpression has been seen in: lymphomas, prostate cancer, melanoma, nasopharyngeal carcinoma, pancreatic cancer, and breast carcinomas. Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer. As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model.
|
|
Rajini Rao is an Indian Physiologist and Professor at Johns Hopkins University School of Medicine. Rao is also the Director of the Graduate Program in Cellular and Molecular Medicine and is the principal investigator of the Rao Lab. Rao discovers novel ion channels and explores their roles in human health and disease. The Rao Lab identified the oncogenic role of SPCA2 in breast cancer through an aberrant method of signalling to calcium channels.
|
|
FHL2 is related to gastrointestinal cancers and in particular, colon cancer. Fhl2 demonstrates an oncogenic property in colon cancer which induces the differentiation of some in vitro colon cancer models. FHL2 is as well crucial to colon cancer cells invasion, migration and adhesion to extracellular matrix. The expression of FHL2 is positively regulated by transforming growth factor beta 1 (TGF-β1) stimulations which induces epithelial-mesenchymal transition (EMT) and endows cancer cells with metastatic properties.
|
|
As reviewed by Kovacevic et al., NDRG1 is a potent, iron-regulated growth and metastasis suppressor that was found to be negatively correlated with cancer progression in a number of tumors, including prostate, pancreatic, breast, and colon cancers. NDRG1 has marked anti- oncogenic activity, being associated with decreased cell proliferation, migration, invasion, and angiogenesis. The molecular functions of NDRG1 affect numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
|
|
Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains (D1 and D2), and thus represents a receptor-type PTP. D1 is catalytically active, while D2 is catalytically inactive.
|
|
CD45 is a pan- leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells, but CD45 positioning within lipid rafts is modified during their oncogenic transformation to acute myeloid leukemia. CD45 colocalizes with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells.
|
|
The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants.
|
|
True single-particle irradiations should allow measurement of the effects of exactly one alpha particle traversal, relative to multiple traversals. The application of such systems to low frequency processes such as oncogenic transformation depends very much on the technology involved. With an irradiation rate of at least 5,000 cells per hour, experiments with yields of the order of 10−4 can practically be accomplished. Hence, high throughput is a desired quality for microbeam systems.
|
|
For instance, neurodegenerative diseases may be affected by m6A as the cognate dopamine signalling was shown to be dependent on FTO and correct m6A methylation on key signalling transcripts. The mutations in HNRNPA2B1, a potential reader of m6A, have been known to cause neurodegeneration. The IGF2BP1–3, a novel class of m6A reader, has oncogenic functions. IGF2BP1–3 knockdown or knockout decreased MYC protein expression, cell proliferation and colony formation in human cancer cell lines.
|
|
A neoantigenic determinant is an epitope on a neoantigen, which is a newly formed antigen that has not been previously recognized by the immune system. Neoantigens are often associated with tumor antigens and are found in oncogenic cells.Neoantigen. (n.d.) Mosby's Medical Dictionary, 8th edition. (2009). Retrieved February 9, 2015 from Medical Dictionary Online Neoantigens and, by extension, neoantigenic determinants can be formed when a protein undergoes further modification within a biochemical pathway such as glycosylation, phosphorylation or proteolysis.
|
|
Additionally, phosphorylation of p27 at T198 by RSK1 has been shown to mislocalize p27 to the cytoplasm as well as inhibit the RhoA pathway. Because inhibition of RhoA results in a decrease in both stress fibers and focal adhesion, cell motility is increased. P27 can also be exported to the cytoplasm by oncogenic activation of the P13K pathway. Thus, mislocalization of p27 to the cytoplasm in cancer cells allows them to proliferate unchecked and provides for increased motility.
|
|
It has been demonstrated that genetic polymorphisms in the TXN2 gene may be associated with the risk of spina bifida. TXN2 is known to inhibit transforming growth factor (TGF)-β-stimulated ROS generation independent of Smad signaling. TGF-β is a pro-oncogenic cytokine that induces epithelial–mesenchymal transition (EMT), which is a crucial event in metastatic progression. In particular, TXN2 inhibits TGF-β- mediated induction of HMGA2, a central EMT mediator, and fibronectin, an EMT marker.
|
|
Simian-T-lymphotropic viruses, also Simian T-cell leukemia viruses (STLVs), are retroviruses closely related to the human sexually and breastfeeding transmissible viruses HTLV. They have subtypes 1 through 4 as compared to HTLV 1 through 4, and each subtype has its own serovars. Together they comprise PTLVs (primate T-lymphotropic viruses) A study has shown that STLV-1 Tax and SBZ proteins have similar functions to their counterparts of HTLV-1. STLV-1 is oncogenic in Japanese macaques.
|
|
Meanwhile, sT has been shown to induce cell proliferation through hyper-phosphorylation of the translation initiator 4EBP1 as well as inhibition of a ubiquitin ligase complex responsible for degradation of cellular proliferation signals. sT also contains a region known as the LT stabilization domain (LSD), which potentiates the LT protein's oncogenic function. Unlike LT, MCC samples have been identified that express sT alone, and sT expression in fibroblasts has been shown to cause MCC phenotype development.
|
|
In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor- associated antigens. Other examples include tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens, cancer-testis antigens and vascular or stromal specific antigens. Tissue differentiation antigens are those that are specific to a certain type of tissue. Mutant protein antigens are likely to be much more specific to cancer cells because normal cells shouldn't contain these proteins.
|
|
Subsequent experiments showed that the normal, cellular Raf genes can also mutate to become oncogenes, by "overdriving" MEK1/2 and ERK1/2 activity. In fact, vertebrate genomes contain multiple Raf genes. Several years later after the discovery of c-Raf, two further related kinases were described: A-Raf and B-Raf. The latter became the focus of research in recent years, since a large portion of human tumors carry oncogenic 'driver' mutations in the B-Raf gene.
|
|
SRP RNA was first detected in avian and murine oncogenic RNA (ocorna) virus particles. Subsequently, SRP RNA was found to be a stable component of uninfected HeLa cells where it associated with membrane and polysome fractions. In 1980, cell biologists purified from canine pancreas an 11S "signal recognition protein" (fortuitously also abbreviated "SRP") which promoted the translocation of secretory proteins across the membrane of the endoplasmic reticulum. It was then discovered that SRP contained an RNA component.
|
|
Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in tumorigenesis. Loss-of-function mutations in the genes encoding succinate dehydrogenase, frequently found in hereditary paraganglioma and pheochromocytoma, cause pathological increase in succinate. SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and neuroblastomas. The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit 2-oxogluterate-dependent dioxygenases.
|
|
This kinase can be activated by insulin, and is necessary for the expression of glucose transporter. Expression of RAS oncogene is found to result in the accumulation of the active form of this kinase, which thus leads to the constitutive activation of MAPK14, and confers oncogenic transformation of primary cells. The inhibition of this kinase is involved in the pathogenesis of Yersinia pseudotuberculosis. Multiple alternatively spliced transcript variants that encode distinct isoforms have been reported for this gene.
|
|
Functional assays of NKX3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of PTEN gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. This indicates that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. It has also been found to be essential in pluripotency of stem cells using Yamanaka factors.
|
|
This protein is implicated in several cancers, including skin cancer, breast cancer, and colorectal cancer. It is a key player in tumor suppression through interactions with oncogenic proteins, including ErbB2 and the p53 tumor suppressor protein. Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 through ubiquitin ligases like MDM2. Moreover, both p53 and DNAJA3 must be present in the mitochondria in order to induce apoptosis in the cell.
|
|
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eukaryotic cells. Its serine/threonine phosphatase activity has a broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as Raf, MEK, and AKT, where PP2A may act as a tumor suppressor.
|
|
Tyrosine-protein phosphatase non-receptor type 2 is an enzyme that in humans is encoded by the PTPN2 gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
|
|
A recent study shows that Par6 associates with PKC-ι but not with PKC-zeta in melanoma. Oncogenic PKC-iota can promote melanoma cell invasion by up- regulating PKC-ι/Par6 pathway during EMT. PKC-ι inhibition or knockdown resulted an increase E-cadherin and RhoA levels while decreasing total Vimentin, phophorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma.
|
|
Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences. USP7 was shown to be important for histone H2B deubiquitination in human cells and for deubiquitination of histone H2B incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression.
|
|
Although over 100 genes mutations have been identified in T-ALL patients, only NOTCH1 and CDKN2A mutations are considered to be common. In over 50% of pediatric T-ALL cases, mutations in epigenetic regulators have been identified. This activates mutations of NOTCH1 and gene FBXW7 causes the tumor-suppressing gene to lose its functions, leading to T-ALL. Near-telomeric location may sometimes generate subtle exchanges in DNA material at the loci involved in oncogenic rearrangements of T-ALL.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This gene is preferentially expressed in a variety of hematopoietic cells, and is an early response gene in lymphokine stimulated cells. The noncatalytic N-terminus of this PTP can interact with MAP kinases and suppress the MAP kinase activities.
|
|
These two findings gave rise to the notion that viral replication and malignant transformation are separate processes in RSV. Rous was awarded the Nobel Prize in Physiology or Medicine for the significance of his discovery in 1966.Nobelprize.org The Nobel Prize in Physiology or Medicine 1966: Peyton Rous, retrieved 1 Jul 2012 Subsequently, after other oncogenic human viruses, such as Epstein-Barr virus, were discovered. Furthermore, oncogenes were found initially in retroviruses and then in cells.
|
|
The src gene is oncogenic as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogene to be discovered. It is an acquired gene, found to be present throughout the animal kingdom with high levels of conservation between species. The src gene was taken up by RSV and incorporated into its genome conferring it with the advantage of being able to stimulate uncontrolled mitosis of host cells, providing abundant cells for fresh infection.
|
|
This oncogenic v-Src is a product of the Rous sarcoma virus and as a result of an carboxy-terminal truncation, v-Src lacks the negative regulatory site Tyr-527 leading this enzyme to be constitutively active that in turn causes uncontrolled growth of infected cells. Moreover, substitution of this tyrosine with phenylalanine in c-Src results in activation. A second regulatory phosphorylation site in Src is Tyr-416. This is an autophosphorylation site in the activation loop.
|
|
TS is considered to be a benign dysplasia, although it can be disfiguring and is sometimes itchy. It is not known whether TS lesions have the potential to develop into cancer; while this outcome has never been reported, some polyomaviruses are oncogenic. The natural history of untreated TS is not known and no long-term studies of its progress have been performed. Improvement in immune function has been reported to resolve symptoms in some individual cases.
|
|
EMT has been shown to be induced by androgen deprivation therapy in metastatic prostate cancer. Activation of EMT programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Oncogenic PKC-iota can promote melanoma cell invasion by activating Vimentin during EMT.
|
|
TrkA was originally cloned from a colon tumor; the cancer occurred via a translocation, which resulted in the activation of the TrkA kinase domain. However, TrkA itself does not appear to be an oncogene. In one study, a total absence of TrkA receptor was found in keratoconus-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor. Gene fusions involving NTRK1 have been shown to be oncogenic, leading to the constitutive TrkA activation.
|
|
Some, but not all, polyomaviruses are oncoviruses capable of inducing neoplastic transformation in some cells. In oncogenic polyomaviruses, the tumor antigens are responsible for the transformation activity, although the exact molecular mechanisms vary from one virus to another. STag is usually not capable of inducing these effects on its own, but increases efficiency of transformation or is sometimes a required component in addition to LTag. In most polyomaviruses, STag's effect on transformation is mediated through its interaction with PP2A.
|
|
EGFR is an oncogenic driver and patients with somatic mutations, particularly an exon 19 deletion or exon 21 L858R mutation, within the tyrosine kinase domain have activating mutations that lead to unchecked cell proliferation. Overexpression of EGFR causes inappropriate activation of the anti-apoptotic Ras signaling pathway, found in many different types of cancer. Icotinib is a quinazoline derivative that binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade.
|
|
The events that lead to genome instability occur in the cell cycle prior to mitosis, specifically in the S phase. Disturbance to this phase can generate negative effects, such as inaccurate chromosomal segregation, for the upcoming mitotic phase. The two processes that are responsible for damage to the S phase are oncogenic activation and tumor suppressor inactivation. They have both been shown to speed up the transition from the G1 phase to the S phase, leading to inadequate amounts of DNA replication components.
|
|
Specifically, mTOR inhibitors have crucial roles in regulating cell growth, cell proliferation and metabolism of highly active tumor cells. Other targeted agents such as MET inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and monoclonal antibodies, are also promising treatment approaches for PRCC. Foretinib is one example of a multikinase inhibitor targeting c-MET. Considering that MET gene mutation is one oncogenic pathway of PRCC, MET inhibitors like tivantinib and volitinib are currently being investigated as a new targeted therapy option.
|
|
PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. Comprehensive, genome-scale analysis has revealed that colorectal carcinomas can be categorized into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF.
|
|
Kaposi's sarcoma People with HIV infections have substantially increased incidence of several cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) (also known as human herpesvirus-8 [HHV-8]), and human papillomavirus (HPV). Kaposi's sarcoma (KS) is the most common tumor in HIV- infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic.
|
|
Receptor-type tyrosine-protein phosphatase H is an enzyme that in humans is encoded by the PTPRH gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and a single intracytoplasmic catalytic domain, and thus represents a receptor-type PTP.
|
|
C7orf43 has also been identified as a target gene of the transcription factor AP-2 gamma (TFAP2C). TFAP2C has been shown to be involved in the development, differentiation, and oncogenesis of mammary tissues. Specifically, TFAP2C has a role in breast carcinoma through its regulatory effect to ESR1 and ERBB2, both of which are receptors whose aberrations have been associated with breast carcinomas. TFAP2C has also been shown to have an oncogenic role by promotion of cell proliferation and tumour growth in neuroblastoma.
|
|
Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing gamma polypeptide is an enzyme that in humans is encoded by the PIK3C2G gene. The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases.
|
|
The protein encoded by this gene is a member of the PTP family and PTPN14 subfamily of tyrosine protein phosphatases. PTPs are known to be signalling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an N-terminal noncatalytic domain similar to that of band 4.1 superfamily cytoskeleton- associated proteins, which suggested the membrane or cytoskeleton localization of this protein. The specific function of this PTP has not yet been determined.
|
|
While HIV/AIDS is associated with a wide range of cancers, including those involving B-cells such as plasmablastic lymphoma, the development of these cancers is commonly attributed to co-infection with oncogenic viruses (e.g. KSHV/HHV8, EBV): the direct role of HIV/AIDS in promoting PEL is unclear. Finally, some studies suggest that EBV cooperates with KSHV/HHV8 to cause PEL, perhaps by enhancing the ability of KSHV/HHV8 to establish their pro-malignant latency phase in infected cells.
|
|
39:653 He identified cellular transcription factors responsible for the expression of viral genes and their functions in regulating cell growth and oncogenic transformation.Yaniv M., « Small DNA tumour viruses and their contributions to our understanding of transcription control », Virology, 2009, p. 384:389 His team established the sequence of the first human Papillomavirus and identified the different genes of the virus.Danos O, et al., « Human papillomavirus 1a complete DNA sequence: a novel type of genome organization among papovaviridae », EMBO J., 1982, 1, p.
|
|
An increased risk of HPV+OPC is observed more than 15 years after HPV exposure, pointing to a slow development of the disease, similar to that seen in cervical cancer. Relative to HPV-OPC, the oncogenic molecular progression of HPV+OPC is poorly understood. The two main viral oncoproteins of the high risk HPV types are E6 and E7. These are consistently expressed in malignant cell lines, and if their expression is inhibited the malignant phenotype of the cancer cells is blocked.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains.
|
|
Tyrosine-protein phosphatase non-receptor type 18 is an enzyme that in humans is encoded by the PTPN18 gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains a PEST motif, which often serves as a protein-protein interaction domain, and may be related to protein intracellular half-live.
|
|
Receptor-type tyrosine-protein phosphatase gamma is an enzyme that in humans is encoded by the PTPRG gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP.
|
|
This gene encodes a member of the highly conserved Aurora subfamily of serine/threonine protein kinases with two other members, Aurora A and Aurora B. The encoded protein is a chromosomal passenger protein that forms complexes with Aurora-B and inner centromere proteins and may play a role in organizing microtubules in relation to centrosome/spindle function during mitosis. This gene is overexpressed in several cancer cell lines, suggesting an involvement in oncogenic signal transduction. Alternative splicing results in multiple transcript variants.
|
|
Secondary structure of ebv- sisRNA-1 In EBV, sisRNAs are generated from a region known as the W repeats. This region is transcribed during a type of viral latency that is highly oncogenic (latency type III) and also in a rare type of latency (Wp-restricted latency) observed in ~15% of endemic Burkitt's lymphoma. Splicing of these W repeat transcripts produces a short intron and a long intron (Fig. 1), both of which accumulate to high abundance in EBV-infected human B cells.
|
|
The drug was first discovered by scientists including Dr. Axel Ullrich and Dr. H. Michael Shepard at Genentech, Inc. in South San Francisco, CA. Earlier discovery about the neu oncogene by Robert Weinberg's lab and the monoclonal antibody recognizing the oncogenic receptor by Mark Greene's lab also contributed to the establishment of HER2 targeted therapies. Dr. Dennis Slamon subsequently worked on trastuzumab's development. A book about Dr. Slamon's work was made into a television film called Living Proof, that premiered in 2008.
|
|
Giet R, Prigent C. Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. Journal of Cell Science 112 (1999) 3591–3601. The human Aurora kinases present a similar domain organization, with a N-terminal domain of 39–129 residues in length, a related Ser/Thr protein kinase domain and a short C-terminal domain containing 15–20 residues. The N-terminal domain of three proteins share low sequence conservation, which determines selectivity during protein–protein interactions.
|
|
Work in Dr. Cafiso's laboratory is directed at studying membranes and peripheral and integral membrane proteins. One area of investigation involves studies on the mechanisms by which proteins become attached to membrane surfaces. Attachment is critical for cell-signaling because it controls protein–protein interactions and the access of enzymes to lipid substrates. For example, the oncogenic form of the src tyrosine kinase is not active and fails to transform cells until it becomes attached to the cytoplasmic face of the plasma membrane.
|
|
Unlike GISTs at other ages, pediatric GISTs are more common in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and PDGFRA. Pediatric GISTs are treated differently than adult GIST. Although the generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, "pediatric-type" GISTs can be seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy.
|
|
Eva Henriette Gottwein is a virologist and Associate Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. The main focus of her research is the role of viral miRNAs involved in herpesviral oncogenesis. Gottwein is member of Lurie Cancer Center at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Her contributions as a member include the focus on how encoded miRNAs target and function in the human oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus known as KSHV.
|
|
The delivery of ISLR-expressing lentivirus into a tumor stroma suppressed the growth of tumors in pancreatic ductal adenocarcinoma (PDAC). In PDAC, low expression of ISLR (Meflin) was associated with aggressive tumors, characterized by straight collagen fibers in the stroma. Regarding tumorigenesis in IBD patients, a study investigated the Hippo signaling pathway in intestinal regeneration of epithelial cells. ETS1, an oncogenic transcription factor in stromal cells, induced the expression of ISLR protein which inhibited Hippo signaling, thus promoting intestinal regeneration.
|
|
Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumors. It is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes. Ras inhibitor trans- farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.
|
|
C/EBPβ function is regulated by multiple mechanisms, including phosphorylation, acetylation, activation, autoregulation, and repression via other transcription factors, oncogenic elements, or chemokines. C/EBPβ can interact with CREB, NF-κB, and other proteins, leading to a trans-activation potential. Phosphorylation of C/EBPβ can have an activation or a repression effect. For example, phosphorylation of threonine 235 in human C/EBPβ, or of threonine 188 in mouse and rat C/EBPβ, is important for C/EBPβ trans-activation capacity.
|
|
CDC25A is specifically degraded in response to DNA damage, resulting in cell cycle arrest. Thus, this degradation represents one axis of a DNA damage checkpoint, complementing induction of p53 and p21 in the inhibition of CDKs. CDC25A is considered an oncogene, as it can cooperate with oncogenic RAS to transform rodent fibroblasts, and it is overexpressed in tumours from a variety of tissues, including breast and head & neck tumours. It is a target of the E2F family of transcription factors.
|
|
Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors. Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways. Pim-1's role in oncogenic signalling has led to it becoming a widely studied target in cancer research, with numerous drug candidates under investigation which target it.
|
|
Tyrosine-protein phosphatase non-receptor type 12 is an enzyme that in humans is encoded by the PTPN12 gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains a C-terminal PEST motif, which serves as a protein–protein interaction domain, and may be related to protein intracellular half-life.
|
|
Specifically, NDRG1 inhibits the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor-light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules including phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4). Through its effects on E-cadherin and beta-catenin, which form the adherens junction and promote cell adhesion, NDRG1 also inhibits the epithelial to mesenchymal transition, an initial key step in metastasis.
|
|
ROS are constantly generated and eliminated in the biological system and are required to drive regulatory pathways. Under normal physiological conditions, cells control ROS levels by balancing the generation of ROS with their elimination by scavenging systems. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids and DNA, leading to fatal lesions in the cell that contribute to carcinogenesis. Cancer cells exhibit greater ROS stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction.
|
|
In this case, miR-17-92 cluster promotes retinoblastoma due to loss of Rb family members. The mouse retinal development need miR-17-92 over-expression with Rb and p107 deletion, but it occurred frequent emergence of retinoblastoma and metastasis to the brain. Here, the cluster oncogenic function is not mediated by a miR-19/PTEN axis toward apoptosis suppression like in lymphoma or in leukemia models. MiR-17-92 increase the proliferative capacity of Rb/p107-deficient in retinal cells.
|
|
Receptor-type tyrosine-protein phosphatase F is an enzyme that in humans is encoded by the PTPRF gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP.
|
|
Chromoplexy refers to a class of complex DNA rearrangement observed in the genomes of cancer cells. This phenomenon was first identified in prostate cancer by whole genome sequencing of prostate tumors. Chromoplexy causes genetic material from one or more chromosomes to become scrambled as multiple strands of DNA are broken and ligated to each other in a new configuration. In prostate cancer, chromoplexy may cause multiple oncogenic events within a single cell cycle, providing a proliferative advantage to a (pre-)cancerous cell.
|
|
Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene. The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of Class II PI 3-kinases.
|
|
The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions.
|
|
Varying functions have been described for this protein. It has been described as a lysosomal hyaluronidase which is active at a pH below 4 and specifically hydrolyzes high molecular weight hyaluronan. It has also been described as a GPI-anchored cell surface protein which does not display hyaluronidase activity but does serve as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression.
|
|
The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress. Most larger cancer treatment centers routinely check for the deletion of 1p/19q as part of the pathology report for oligodendrogliomas. The status of the 1p/19q loci can be detected by FISH, loss of heterozygosity (LOH) analysis or virtual karyotyping.
|
|
Accessory genes are located between pol and env, downstream from the env, including the U3 region of LTR, or in the env and overlapping portions. While accessory genes have auxiliary roles, they also coordinate and regulate viral gene expression. In addition, some retroviruses may carry genes called oncogenes or onc genes from another class. Retroviruses with these genes (also called transforming viruses) are known for their ability to quickly cause tumors in animals and transform cells in culture into an oncogenic state.
|
|
Human papilloma virus is a common and widespread disease that, if left untreated, can lead to epithelial lesions and cervical cancer. HPV infection inhibits the expression of TLR9 in keratinocytes, abolishing the production of IL-8. However inhibition of TLR9 by oncogenic viruses is temporary, and patients with long-lasting HPV actually show higher levels of TLR9 expression in cervical cells. In fact, the increase in expression is so severe that TLR9 could be used as a biomarker for cervical cancer.
|
|
As many as 20% of human tumors are caused by viruses. Some such viruses that are commonly recognized include HPV, T-cell Leukemia virus type I, and hepatitis B. Viral oncogenesis are most common with DNA and RNA tumor viruses, most frequently the retroviruses. There are two types of oncogenic retroviruses: acute transforming viruses and non-acute transforming viruses. Acute transforming viruses induce a rapid tumor growth since they carry viral oncogenes in their DNA/RNA to induce such growth.
|
|
While double-stranded breaks in the DNA can be caused by various sources of disruption, they are often observed at high frequency during apoptosis and can contribute to genome instability, resulting in oncogenic mutations. For this reason, high-resolution, specific DSB-mapping methods like BLESS are useful for breakome surveys. DSBs can be artificially induced using genome editing technologies such as CRISPR-Cas9 or TALEN. These technologies may lead to unintentional modifications of DNA at off-target locations on the genome.
|
|
The cellular receptor for JSRV is hyaluronidase 2 (Hyal2), a glycophosphatidylinol(GPI)-anchored protein belonging to the hyaluronidase family. Generally, oncogenic retroviruses cause transformation of host cells mostly by insertional activation of a host protooncogene into an oncogene. But JSRV is different in this aspect since its envelope glycoprotein ("env") by itself is an oncogene and this single protein was shown to be necessary and sufficient to induce lung tumors in sheep. Unlike the majority of retroviruses, JSRV entry into the host cell is pH-dependent.
|
|
Tether containing UBX domain for GLUT4 (TUG) is a protein that in humans is encoded by the ASPSCR1 gene. This gene is a candidate gene for alveolar soft part sarcoma (ASPS). It has been found that ASPSCR1 can undergo oncogenic rearrangement with transcription factor TFE3 gene, creating an aberrant gene that is a stronger transcriptional activator than TFE3 alone. This fusion oncogene encodes for a chimeric transcription factor, which is responsible for the production of multiple molecules that contribute to ASPS and also to renal cell carcinomas.
|
|
It has been shown that CD97 regulates localization and degradation of β-catenin. GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes. Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.
|
|
Activation of the oncogenic transcription factor gene MYB is the key genomic event of ACC and seen in the vast majority of cases. Most commonly, MYB is activated through gene fusion with the transcription factor encoding NFIB gene as a result of a t(6;9) translocation. Alternatively, MYB is activated by copy number gain or by juxtaposition of enhancer elements in the vicinity of the MYB gene. In a subset of ACCs, the closely related MYBL1 gene is fused to NFIB or to other fusion partners.
|
|
P27 is considered a tumor suppressor because of its function as a regulator of the cell cycle. In cancers it is often inactivated via impaired synthesis, accelerated degradation, or mislocalization. Inactivation of p27 is generally accomplished post-transcription by the oncogenic activation of various pathways including receptor tyrosine kinases (RTK), phosphatilidylinositol 3-kinase (PI3K), SRC, or Ras-mitogen activated protein kinase(MAPK). These act to accelerate the proteolysis of the p27 protein and allow the cancer cell to undergo rapid division and uncontrolled proliferation.
|
|
RNase P is now being studied as a potential therapy for diseases such as herpes simplex virus, cytomegalovirus, influenza and other respiratory infections, HIV-1 and cancer caused by fusion gene BCR- ABL. External guide sequences (EGSs) are formed with complementarity to viral or oncogenic mRNA and structures that mimic the T loop and acceptor stem of tRNA. These structures allow RNase P to recognize the EGS and cleave the target mRNA. EGS therapies have shown to be effective in culture and in live mice.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an N-terminal domain, similar to cytoskeletal- associated proteins including band 4.1, ezrin, merlin, and radixin. This PTP was shown to specially interact with BMX/ETK, a member of Tec tyrosine kinase family characterized by a multimodular structures including PH, SH3, and SH2 domains.
|
|
Large scale studies such as The Cancer Genome Atlas have characterized recurrent somatic alterations likely driving initiation and development of cutaneous melanoma. The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). BRAF is normally involved in cell growth and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth. RAS genes (NRAS, HRAS and KRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity.
|
|
NDV possesses many unique anticancer properties and thereby provides an excellent base in virotherapy research. NDV has selectivity on oncogenic cells, where it replicates without, or in a less pronounced way, harming normal cells. It binds, fuses into and replicates within the infected cells’ cytoplasm independent of cell proliferation. One of the main issues using NDV treatment is the host/patient immune response against the virus itself, which prior to the time of the reverse genetics technology, decreased the applicability of NDV as a cancer treatment.
|
|
1999 Oct;23(2):166-75. In addition, RUNX1 mutations have also been reported in Acute myeloid leukemia (AML).Haematologica. 2007 Aug;92(8):1123-6Blood. 2009 Oct 1;114(14):3001-7 The RUNX1 and CBFB genes are targets of chromosome rearrangements that create oncogenic fusion genes in leukemia. The chromosome translocation t(12;21) (p13.1;q22) causes the fusion of the ETS variant 6 (ETV6) and RUNX1 genes results in ETV6-RUNX1 gene fusion and is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL).
|
|
Translational control is critical for the development and survival of cancer. Cancer cells must frequently regulate the translation phase of gene expression, though it is not fully understood why translation is targeted over steps like transcription. While cancer cells often have genetically altered translation factors, it is much more common for cancer cells to modify the levels of existing translation factors. Several major oncogenic signaling pathways, including the RAS–MAPK, PI3K/AKT/mTOR, MYC, and WNT–β-catenin pathways, ultimately reprogram the genome via translation.
|
|
Hunter is one of the foremost recognized leaders in the field of cell growth control, growth factor receptors and their signal transduction pathways. He is well known for discovering that tyrosine phosphorylation is a fundamental mechanism for transmembrane-signal transduction in response to growth factor stimulation and that disregulation of such tyrosine phosphorylation, by activated oncogenic protein tyrosine kinases, is a pivotal mechanism utilized in the malignant transformation of cells. His work is important in signaling pathways and their disorders. Hunter was a founder of Signal Pharmaceuticals.
|
|
Ras GTPase-activating protein 3 is an enzyme that in humans is encoded by the RASA3 gene. The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal- associated proteins. P97, a cell cycle regulator involved in a variety of membrane related functions, has been shown to be a substrate of this PTP.
|
|
These include stimulation with growth factors/cytokines/chemokines, or DNA damage reagents. Furthermore, THOC5 is a substrate for several oncogenic tyrosine kinases, suggesting that THOC5 may be involved in cancer development. Recent THOC5 knockout mouse data reveal that THOC5 is an essential element in the maintenance of stem cells and growth factor/cytokine-mediated differentiation/proliferation. Furthermore, depletion of THOC5 influences less than 1% of total mRNA export in the steady state, however it influences more than 90% of growth factor/cytokine induced genes.
|
|
Nocodazole is an antineoplastic agent which exerts its effect in cells by interfering with the polymerization of microtubules. Microtubules are one type of fibre which constitutes the cytoskeleton, and the dynamic microtubule network has several important roles in the cell, including vesicular transport, forming the mitotic spindle and in cytokinesis. Several drugs including vincristine and colcemid are similar to nocodazole in that they interfere with microtubule polymerization. Nocodazole has been shown to decrease the oncogenic potential of cancer cells via another microtubules- independent mechanisms.
|
|
In animals these kinases have reported roles in the regulation of diverse processes, including cell proliferation control, activity of proto-oncogenic proteins, apoptosis, centrosome duplication, and organization of neuronal dendrites. In unicellular eukaryotes, Ndr kinases play important roles in the control of the cell cycle and morphogenesis. In the fission yeast Schizosaccharomyces pombe, an organism amenable for the study of cell morphogenesis, the Ndr kinase Orb6 has a role in cell polarity and morphogenesis control in part by the regulation of small Rho-type GTPase Cdc42.
|
|
Tang W.K., Chui C.H., Fatima S., Kok S.H., Pak K.C., Ou T.M., Hui K.S., Wong M.M., Wong J., Law S., Tsao S.W., Lam K.Y., Beh P.S., Srivastava G., Ho K.P., Chan A.S., Tang J.C. (2007). "Inhibitory effects of Gleditsia sinensis fruit extract on telomerase activity and oncogenic expression in human esophageal squamous cell carcinoma." International Journal of Molecular Medicine. 19(6):953-960.Chui C.H., Gambari R., Lau F.Y., Teo I.T.N., Ho K.P., Cheng G.Y.M., Ke B., Higa T., Kok H.L., Chan A.S.C., Tang J.C.O. (2005).
|
|
While ARHI is structurally similar to other GTPase proteins, its function is remarkably different from Ras. Ras is an oncogenic protein involved in cellular proliferation and signal transduction, and while the Ras superfamily generally consists of positive growth regulators, ARHI is a tumor-suppressor gene. In contrast to Ras, ARHI works as an inhibitor for cell growth, thus functioning as a negative growth regulator. ARHI has also been shown to have less GTPase activity than most Ras proteins even though the proteins share a very similar structure.
|
|
Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes. Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun’s activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation. Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.
|
|
Antibodies against Esa1p specifically immunoprecipitate NuA4 activity whereas the complex purified from a temperature-sensitive esa1 mutant loses its acetyltransferase activity at the restrictive temperature. Additionally, another subunit of the complex has been identified as the product of TRA1, an ATM-related essential gene homologous to human TRRAP, an essential cofactor for c-Myc- and E2F-mediated oncogenic transformation. Finally, the ability of NuA4 to stimulate GAL4–VP16-driven transcription from chromatin templates in vitro is also lost in the temperature-sensitive esa1 mutant.
|
|
Aberrant Notch signaling is a driver of T cell acute lymphoblastic leukemia (T-ALL) and is mutated in at least 65% of all T-ALL cases. Notch signaling can be activated by mutations in Notch itself, inactivating mutations in FBXW7 (a negative regulator of Notch1), or rarely by t(7;9)(q34;q34.3) translocation. In the context of T-ALL, Notch activity cooperates with additional oncogenic lesions such as c-MYC to activate anabolic pathways such as ribosome and protein biosynthesis thereby promoting leukemia cell growth.
|
|
Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases, Ras or Raf proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit Raf kinases (e.g. Sorafenib) are successful antineoplastic agents against various types of cancer.
|
|
Indole-3-carbinol causes proliferation arrest and apoptosis in human melanoma cells. Kim YS et al showed that the master regulator of melanoma biology, microphthalmia-associated transcription factor (MITF-M) was downregulated by Indole-3-carinol to induce apoptosis. Kundu A et al demonstrated that the anticancer property of Indole-3-carbinol is driven by specific targeting of oncogenic pathways. In two different studies using xenografted mouse model of melanoma, they observed that subcutaneous injection of Indole-3-carbinol could bring down tumor burden significantly.
|
|
Interleukin 6 (acronym: IL-6) is a cytokine that is important for many aspects of cellular biology including immune responses, cell survival, apoptosis, as well as proliferation. Several studies have outlined the importance of autocrine IL-6 signaling in lung and breast cancers. For example, one group found a positive correlation between persistently activated tyrosine-phosphorylated STAT3 (pSTAT3), found in 50% of lung adenocarcinomas, and IL-6. Further investigation revealed that mutant EGFR could activate the oncogenic STAT3 pathway via upregulated IL-6 autocrine signaling.
|
|
Nuclear bodies include Cajal bodies, the nucleolus, and promyelocytic leukemia protein (PML) nuclear bodies (also called PML oncogenic dots). Nuclear bodies also include ND10s. ND stands for nuclear domain, and 10 refers to the number of dots seen. Nuclear bodies were first seen as prominent interchromatin structures in the nuclei of malignant or hyperstimulated animal cells identified using anti-sp100 autoantibodies from primary biliary cirrhosis and subsequently the promyelocytic leukemia (PML) factor, but appear also to be elevated in many autoimmune and cancerous diseases.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and a single intracellular catalytic domains, and thus represents a receptor-type PTP. The similar gene predominately expressed in mouse brain was found to associate with, and thus regulate the activity and cellular localization of MAP kinases.
|
|
RBM10 suppresses cell proliferation and promotes apoptosis. Hence, it is generally regarded as a tumor suppressor. However, in certain cases, it may exert an opposite oncogenic function by acting as a tumor promoter or growth enhancer, presumably due to the cellular contexts composed of different constituents and active pathways. A typical example of this is patients with pancreatic ductal adenocarcinoma (PDAC) having RBM10 mutations, who exhibit a survival rate remarkably higher than the general 5-year PDAC survival rate of less than 7–8%.
|
|
The protein product of this gene, best known as CD45, is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. CD45 contains an extracellular domain, a single transmembrane segment, and two tandem intracytoplasmic catalytic domains, and thus belongs to the receptor type PTP family. CD45 is a type I transmembrane protein that is present in various isoforms on all differentiated hematopoietic cells (except erythrocytes and plasma cells).
|
|
Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis. This drug has been reported to reduce the frequency of regulatory T cells (T-Reg) and after converting from a CNI monotherapy to a mycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.Ahmet Demirkiran et.
|
|
It has been found to be oncogenic and is implicated in cervical cancers. PIK3CA mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date. While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal- associated proteins. This PTP has been shown to interact with glutamate receptor delta 2 and epsilon subunits, and is thought to play a role in signalling downstream of the glutamate receptors through tyrosine dephosphorylation.
|
|
However, in murine models, novel genetic methods have allowed for in vivo Rb reactivation experiments. Rb loss induced in mice with oncogenic KRAS-driven tumors of lung adenocarcinoma negates the requirement of MAPK signal amplification for progression to carcinoma and promotes loss of lineage commitment as well as accelerate the acquisition of metastatic competency. Reactivation of Rb in these mice rescues the tumors towards a less metastatic state, but does not completely stop tumor growth due to a proposed rewiring of MAPK pathway signaling, which suppresses Rb through a CDK-dependent mechanism.
|
|
HTLV-1 causes an aggressive form of leukaemia: adult T cell leukaemia (ATL), and Tax has largely been implicated in the oncogenic potential of this virus. In addition to Tax's ability to promote the transcription of viral proteins in the nucleus, it also regulates many human genes. It does this by modulating the activity of several signaling pathways such as: CREB/ATF, NF-κB, AP-1 and SRF. Tax modulates cellular processes by protein-protein interaction (binding with proteins), transcriptional activation (promoting the production of proteins) and transcriptional repression (inhibiting the production of proteins).
|
|
Many proteins are involved in these processes, including cyclins and cell cycle checkpoint proteins (p53 and Rb). Interesting, HTLV-1 Tax viral gene is known to dampen innate antiviral signaling pathways to avoid host detection and elimination, through SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP). Although Tax from HTLV-1 and HTLV-2 can cause cells to become cancerous experimentally, Tax produced by HTLV-2 is less oncogenic than that from HTLV-1 and therefore is thought to be the reason that HTLV-2 is not associated with ATL.
|
|
Due to a close similarity in the gene sequences, the protein encoded by this gene has traditionally been considered a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. However, recent research has shown that the PTPRN2 mouse homolog, known as phogrin, dephosphorylates the lipid phosphatidylinositol rather than tyrosine. Specifically, phogrin was shown to act upon phosphatidylinositol 3-phosphate and Phosphatidylinositol 4,5-diphosphate, whereas it has never been observed acting upon tyrosine.
|
|
This serves two oncogenic purposes: first, it prevents successful viral replication that would culminate in lysis of the infected cell. Second, it redistributes the LT protein to the cytoplasm, where it can interact with cytoplasmic signaling. The N-terminal LXCXE motif of the LT protein has been shown to interact with known oncogene Rb and is conserved in other cancer- causing viruses. Studies suggest that LT may also preserve cell proliferation signals such as c-Myc and cyclin E and cause DNA injury to the p53 tumor suppressor.
|
|
In healthy human cells the virus cannot reproduce, likely because of the interferon response, which allows the cells to adequately respond to viral infection. The same cannot be said of interferon non-responsive cancer cells, a quality which allows VSIV to grow and lyse oncogenic cells preferentially. Recently, attenuated VSIV with a mutation in its M protein has been found to have oncolytic properties. Research is ongoing, and has shown VSIV to reduce tumor size and spread in melanoma, lung cancer, colon cancer and certain brain tumors in laboratory models of cancer.
|
|
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
|
|
Micrographs of loose, moderate and dense desmoplastic stroma in pancreatic ductal adenocarcinoma, as seen with H&E; stain (top row), Masson's trichrome stain (middle row) and α-smooth muscle actin. Cancer begins as cells that grow uncontrollably, usually as a result of an internal change or oncogenic mutations within the cell. Cancer develops and progresses as the microenvironment undergoes dynamic changes. The stromal reaction in cancer is similar to the stromal reaction induced by injury or wound repair: increased ECM and growth factor production and secretion, which consequently cause growth of the tissue.
|
|
Activation of PDGFRB, a third member of the type III RTK family, has been implicated in the development of chronic myelomonocytic leukemia due to the fusion of PDGFRB with the TEL gene. Furthermore, PDGFB translocation to the COL1A1 gene locus has been identified to be responsible for dermatofibrosarcoma protuberans (DFSP). In cancer cells, PDGFR promotes tumor development and migration via proto-oncogenic downstream mediators like AKT and MEK. In stromal fibroblasts, PDGFRα activation leads to local tissue invasion, production and secretion of VEGF, and elevated intratumoral interstitial pressure.
|
|
Dysfunction of cell adhesion occurs during cancer metastasis. Loss of cell–cell adhesion in metastatic tumour cells allows them to escape their site of origin and spread through the circulatory system. One example of CAMs deregulated in cancer are cadherins, which are inactivated either by genetic mutations or by other oncogenic signalling molecules, allowing cancer cells to migrate and be more invasive. Other CAMs, like selectins and integrins, can facilitate metastasis by mediating cell–cell interactions between migrating metastatic tumour cells in the circulatory system with endothelial cells of other distant tissues.
|
|
For example, siRNA from double strand breaks (produced by Dicer) may act as guides for protein complexes involved in the double strand break repair mechanisms and can also direct chromatin modifications. Additionally, miRNAs expression patterns change as a result of DNA damage caused by ionizing or ultraviolet radiation. RNAi mechanisms are responsible for transposon silencing and in their absence, as when Dicer is knocked out/down, can lead to activated transposons that cause DNA damage. Accumulation of DNA damage may result in cells with oncogenic mutations and thus the development of a tumor.
|
|
Pritchard moved to the University of Leicester where she held a Royal Society University Research Fellow from 1995–2003. She began to use genetic mouse models to investigate the role of the RAF family of protein kinases in control of intracellular signalling pathways involved in mammalian development. She developed conditional knockin mouse models for oncogenic forms of BRAF detected in human cancer and used these models to understand mechanisms of oncogene-driven cancer initiation and progression. The majority of this work was supported by Cancer Research UK programme funding.
|
|
There are high-risk HPV types, that are not affected by available vaccines. Ongoing research is focused on the development of HPV vaccines that will offer protection against a broader range of HPV types. One such method is a vaccine based on the minor capsid protein L2, which is highly conserved across HPV genotypes. Efforts for this have included boosting the immunogenicity of L2 by linking together short amino acid sequences of L2 from different oncogenic HPV types or by displaying L2 peptides on a more immunogenic carrier.
|
|
Demonstration of the link between hPG80 and an oncogenic pathway has been described for K-Ras. Cell lines and colon cancer tissues with K-Ras mutations all had significantly higher levels of GAST mRNA than wild type K-Ras. K-Ras effects on GAST expression are produced by activation of the Raf-MEK-ERK signal transduction pathway, final step being activation of the GAST gene promoter. Since both K-Ras and the Wnt pathway induce GAST expression, the hypothesis of a possible cooperation between these two pathways to regulate hPG80 expression was investigated.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells.
|
|
Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic (chromosome-breaking) and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
|
|
As a consequence of immunoediting, tumor cell clones less responsive to the immune system gain dominance in the tumor through time, as the recognized cells are eliminated. This process may be considered akin to Darwinian evolution, where cells containing pro-oncogenic or immunosuppressive mutations survive to pass on their mutations to daughter cells, which may themselves mutate and undergo further selective pressure. This results in the tumor consisting of cells with decreased immunogenicity and can hardly be eliminated. This phenomenon was proven to happen as a result of immunotherapies of cancer patients.
|
|
Oncogenic retroviridae proteins are retroviral proteins that have the ability to transform cells. They can induce sarcomas, leukaemias, lymphomas, and mammary carcinomas. These include the gag-onc fusion protein, rex, tax, v-fms, ras, v-myc, v-src, v-akt, v-cbl, v-crk, v-maf, v-abl, v-erbA, v-erbB, v-fos, v-mos, v-myb, v-raf, v-rel, and v-sis. The "v" prefix indicates viral genes which once originated as similarly named genes of the host species, but have since been altered through independent evolution as retroviral components.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. This PTP has been shown to dephosphorylate and activate Src family tyrosine kinases, and is implicated in the regulation of integrin signaling, cell adhesion and proliferation.
|
|
The 2;5 chromosomal translocation is associated with approximately 60% anaplastic large-cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3.
|
|
SFRS1 is a proto-oncogene, and thus ASF/SF2 can act as an oncoprotein; it can alter the splicing patterns of crucial cell cycle regulatory genes and suppressor genes. ASF/SF2 controls the splicing of various tumor suppressor genes, kinases, and kinase receptors, all of which have the potential to be alternatively spliced into oncogenic isoforms. As such, ASF/SF2 is an important target for cancer therapy, as it is over-expressed in many tumors. Modifications and defects in the alternative splicing pathway are associated with a variety of human diseases.
|
|
As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae). Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes. For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc. In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types.
|
|
Several oncogenic mutations in prostate cancer occur through chromoplexy, such as disruption of the tumor suppressor gene PTEN or creation of the TMPRSS2-ERG fusion gene. Chromplexy was originally inferred by statistically analyzing the location of DNA breaks across the genome. Its prevalence across cancers is not known, because only a few types of tumors have been analyzed for chromoplexy in the published literature. However, it was detected in the majority of 57 prostate tumors analyze and has been reported in non-small cell lung cancers, melanoma and head and neck squamous cell cancers.
|
|
The translocation of phosphorylated Smad3 into the nucleus allows for direct interaction with EVI1, mediated by the first zinc finger domain on EVI1 and the MH2 domain on Smad3. As the Smad3 MH2 domain is required for transcription activation, EVI1 binding effectively prevents transcription of the TGF-β induced anti-growth genes through structural blocking, and also leads to recruitment of other transcriptional repressors (see Epigenetics). By inhibiting an important checkpoint pathway for tumor suppression and growth control, overexpression or aberrant expression of EVI1 has characteristic oncogenic activity.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family and PTPRN subfamily. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and a single catalytic domain, and thus represents a receptor-type PTP. This PTP was found to be an autoantigen that is reactive with insulin-dependent diabetes mellitus (IDDM) patient sera, and thus may be a potential target of autoimmunity in diabetes mellitus.
|
|
Exploitation of this channel is advantageous in cancer cell survival as they have the ability to produce heme oxygenase-1, an enzyme with the ability to generate carbon monoxide (CO). Oncogenic cells benefit from producing CO due to the antagonizing effects of the KCNB1 channel. Inhibition of KCNB1 allows cancer proliferation without the apoptotic pathway preventing tumor formation. Although potassium channels are studied as a therapeutic target for cancer, this apoptotic regulation is dependent on cancer type, potassium channel type, expression levels, intracellular localization as well as regulation by pro- or anti-apoptotic factors.
|
|
The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins, a family of 50 to 100 proteins, are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene belongs to the nucleoporin family and is associated with the oncogenic nucleoporin CAN/Nup214 in a dynamic subcomplex. This protein is also overexpressed in a large number of malignant neoplasms and precancerous dysplasias.
|
|
Tyrosine kinases of Src family contain the same typical structure: myristoylated terminus, a region of positively charged residues, a short region with low sequence homology, SH3 and SH2 domains, a tyrosine kinase domain, and a short carboxy-terminal tail. There are two important regulatory tyrosine phosphorylation sites. To repress kinase activity it is possible by phosphorylation of Tyr-527 in the carboxy-terminal tail of Src by the nRTK Csk. By the experiment of v-Src, an oncogenic variant of Src, the importance of this phosphorylation site was confirmed.
|
|
Expression of the c-myc gene, which produces an oncogenic transcription factor, is tightly regulated in normal cells but is frequently deregulated in human cancers. The protein encoded by this gene is a transcriptional repressor thought to negatively regulate MYC function, and is therefore a potential tumor suppressor. This protein inhibits the transcriptional activity of MYC by competing for MAX, another basic helix- loop-helix protein that binds to MYC and is required for its function. Defects in this gene are frequently found in patients with prostate tumors.
|
|
When a tumor stimulates the growth of new vessels, it is said to have undergone an 'angiogenic switch'. The principal stimulus for this angiogenic switch appears to be oxygen deprivation, although other stimuli such as inflammation, oncogenic mutations and mechanical stress may also play a role. The angiogenic switch leads to tumor expression of pro-angiogenic factors and increased tumor vascularization. Specifically, tumor cells release various pro-angiogenic paracrine factors (including angiogenin, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β).
|
|
There is also the unlikely possibility that the engineered CAR-T cells will themselves become transformed into cancerous cells through insertional mutagenesis, due to the viral vector inserting the CAR gene into a tumor suppressor or oncogene in the host T cell's genome. Some retroviral (RV) vectors carry a lower risk than lentiviral (LV) vectors. However, both have the potential to be oncogenic. Genomic sequencing analysis of CAR insertion sites in T cells has been established for better understanding of CAR T cell function and persistence in vivo.
|
|
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain- containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2. PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
|
|
Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors. Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma. Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins.
|
|
Oncogenic types of the human papillomavirus (HPV) are known to hijack cellular ubiquitin-proteasome pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind p53, a well-known tumor suppressor gene that inactivation is found in many types of cancer. Thus, p53 undergoes ubiquitination and proteasome- mediated degradation. Meanwhile, E7, another one of the early-expressed HPV genes, will bind to Rb, also a tumor suppressor gene, mediating its degradation.
|
|
In 1993, five patients with pancreatic cancer received ras peptide vaccines carrying mutations in codon 12. The five patients carried the corresponding Ras mutation and Ras-specific T cell responses were induced in two of the patients. The study demonstrated that specific T cell responses against mutations uniquely harbored in tumor cells can be induced in cancer patients by vaccination. Furthermore, late stage pancreatic cancer patients from two previous phase I/II clinical studies, which received K-ras derived peptides carrying oncogenic mutations, were followed more than 10 years.
|
|
Together, their broad inhibitory role may help counter oncogenic signals. As mentioned above, INK4a inhibits proliferation by indirectly allowing Rb to remain associated with E2F transcription factors. ARF is involved in p53 activation by inhibiting Mdm2 (HDM2 in humans). Mdm2 binds to p53, inhibiting its transcriptional activity. Mdm2 also has E3 ubiquitin ligase activity toward p53, and promotes its exportation from the cell nucleus to the cytoplasm for degradation. By antagonizing Mdm2, ARF permits the transcriptional activity of p53 that would lead to cell cycle arrest or apoptosis.
|
|
ARF expression is regulated by oncogenic signaling. Aberrant mitogenic stimulation, such as by MYC or Ras (protein), will increase its expression, as will an amplification of mutated p53 or Mdm2, or p53 loss. ARF can also be induced by enforced E2F expression. Although E2F expression is increased during the cell cycle, ARF expression probably is not because the activation of a second, unknown transcription factor might be needed to prevent an ARF response to transient E2F increases. ARF is negatively regulated by Rb-E2F complexes and by amplified p53 activation.
|
|
This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cancer of the cervix, vulva, vagina, penis, anus, mouth, and throat, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells.
|
|
Xue et al., RNAi was used to regulated endogenous p53 in a liver carcinoma model. Xue et al. utilized a chimaeric liver cancer mouse model and transduced this model with the ras oncogene. They took embryonic progenitor cells, transduced those cells with oncogenic ras, along with the tetracycline transactivator (tta) protein to control p53 expression using doxycycline, a tetracycline analog and tetracycline responsive short hairpin RNA (shRNA). In the absence of Dox, p53 was actively suppressed as the microRNA levels increased, so as Dox was administered, p53 microRNA was turned off to facilitate the expression of p53.
|
|
The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an N-terminal domain that shares a significant similarity with yeast SEC14, which is a protein that has phosphatidylinositol transfer activity and is required for protein secretion through the Golgi complex in yeast. This PTP was found to be activated by poly-phosphoinositide, and is thought to be involved in signaling events regulating phagocytosis.
|
|
Carlo Gambacorti-Passerini Carlo Gambacorti-Passerini (born 26 August 1957) is an Italian oncologist and hematologist known for his contributions to cancer research. He is Professor of Internal Medicine and Hematology at the University of Milan Bicocca in Italy and Director of the Hematology Department at S. Gerardo Hospital, Monza, Italy. He was Senior Investigator and Head of the Oncogenic Fusion Proteins Unit at the National Cancer Institute, Milan Italy from 1990 to 2003, and Professor of Oncology and Hematology at McGill University, Montreal, Quebec, Canada, from 2004 to 2007. His main scientific contribution relates to the preclinical and clinical development of imatinib.
|
|
Normally, G proteins are regulated by GAP, which results in controlled cell division. Often, this oncogenic behavior is due to a loss of function of GAPs associated with those G proteins or a loss of the G protein's ability to respond to its GAP. With the former, G proteins are unable to hydrolyze GTP quickly, resulting in sustained expression of the active form of G proteins. Although the G proteins have weak hydrolytic activity, in the presence of functional GEFs, the inactivated G proteins are constantly replaced with activated ones because the GEFs exchange GDP for GTP in these proteins.
|
|
The first study to use this digestion to study the relevance of chromatin accessibility to gene expression in humans was in 1985. In this study, nuclease was used to find the association of certain oncogenic sequences with chromatin and nuclear proteins. Studies utilizing MNase digestion to determine nucleosome positioning without sequencing or array information continued into the early 2000s. With the advent of whole genome sequencing in the late 1990s and early 2000s, it became possible to compare purified DNA sequences to the eukaryotic genomes of S. cerevisiae, Caenorhabditis elegans, D. melanogaster, Arabidopsis thaliana, Mus musculus, and Homo sapiens.
|
|
The success of gene therapy depends on the efficient insertion of therapeutic genes at the appropriate chromosomal target sites within the human genome, without causing cell injury, oncogenic mutations or an immune response. The construction of plasmid vectors is simple and straightforward. Custom-designed ZFNs that combine the non-specific cleavage domain (N) of FokI endonuclease with zinc-finger proteins (ZFPs) offer a general way to deliver a site- specific DSB to the genome, and stimulate local homologous recombination by several orders of magnitude. This makes targeted gene correction or genome editing a viable option in human cells.
|
|
To overcome imatinib resistance and to increase responsiveness to TK inhibitors, four novel agents were later developed. The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR- ABL protein, and was initially approved in 2007 by the US FDA to treat CML in patients who were either resistant to or intolerant of imatinib. A second new TK inhibitor, nilotinib, was also approved by the FDA for the same indication. In 2010, nilotinib and dasatinib were also approved for first-line therapy, making three drugs in this class available for treatment of newly diagnosed CML.
|
|
Adenoviruses can lead to tumors in rodent models but do not cause cancer in humans; however, they have been exploited as delivery vehicles in gene therapy for diseases such as cystic fibrosis and cancer. Simian virus 40 (SV40), a polyomavirus, can cause tumors in rodent models but is not oncogenic in humans. This phenomenon has been one of the major controversies of oncogenesis in the 20th century because an estimated 100 million people were inadvertently exposed to SV40 through polio vaccines. The human papillomavirus-16 (HPV-16) has been shown to lead to cervical cancer and other cancers, including head and neck cancer.
|
|
Since c-jun has been observed overexpressed in cancer, several studies highlighted the hypothesis that this gene might be a target for cancer therapy. A study showed that oncogenic transformation by ras and fos requires Jun N-terminal phosphorylation at Serine 63 and 73 by the Jun N- terminal kinases (JNK). In this study, the induced skin tumor and osteosarcoma showed impaired development in mice with a mutant Jun incapable of N-terminal phosphorylation. Also, in a mouse model of intestinal cancer, genetic abrogation of Jun N-terminal phosphorylation or gut-specific c-jun inactivation attenuated cancer development and prolonged lifespan.
|
|
The Notch protein spans the cell membrane, with part of it inside and part outside. Ligand proteins binding to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which enters the cell nucleus to modify gene expression. The cleavage model was first proposed in 1993 based on work done with Drosophila Notch and C. elegans lin-12, informed by the first oncogenic mutation affecting a human Notch gene. Compelling evidence for this model was provided in 1998 by in vivo analysis in Drosophila by Gary Struhl and in cell culture by Raphael Kopan.
|
|
K-Ras(G12C) inhibitor 6 is an irreversible inhibitor of oncogenic K-Ras(G12C), subverting the native nucleotide preference to favour GDP over GTP. Its family of inhibitors allosterically control GTP affinity and effector interactions by fitting inside a "pocket", or binding site, of mutant K-Ras. Investigators and pathologists previously thought that K-Ras is undruggable. However, Kevan M. Shokat and his colleagues, in the Howard Hughes Medical Institute (HHMI) at the University of California, recently reported a novel discovery of "Achilles heel" on K-RAs, and believed that it has real translational implications for patients with K-RAs mutation.
|
|
They are targeted against oncogenic receptors such as epidermal growth factor receptor (EGFR). Tumor eradication resulted when PD-L1 (also induced by IFN-β acting on DCs) was neutralized. DC function also may be adversely affected by the TME's hypoxic conditions, which induces PD-L1 expression on DCs and other myelomonocytic cells as a result of hypoxia-inducible factors-1α (HIF-1α) binding directly to a hypoxia-responsive element in the PD-L1 promoter. Even the aerobic glycolysis of cancer cells may antagonize local immune reactions via increasing lactate production, which induces the M2 TAM polarization.
|
|
This abnormal stimulation of the cell cycle is a powerful force for oncogenic transformation. The small tumor antigen protein is also able to activate several cellular pathways that stimulate cell proliferation. Polyomavirus small T antigens commonly target protein phosphatase 2A (PP2A), a key multisubunit regulator of multiple pathways including Akt, the mitogen- activated protein kinase (MAPK) pathway, and the stress-activated protein kinase (SAPK) pathway. Merkel cell polyomavirus small T antigen encodes a unique domain, called the LT-stabilization domain (LSD), that binds to and inhibits the FBXW7 E3 ligase regulating both cellular and viral oncoproteins.
|
|
He showed that transformation by Ras requires interaction with multiple effectors, which contribute differentially to cell cycle progression, cytoskeletal regulation and apoptosis. His work has established that both cell matrix and cell–cell interaction activate the PI 3-kinase/PKB pathway, and thereby prevent programmed cell death, and that it is activation of this pathway by oncogenic Ras that allows anchorage- independent growth of transformed cells. Most recently he has focused on identifying unique weaknesses of cancer cells expressing the activated Ras oncogene using a combination of large-scale functional genomics and pre- clinical models of lung cancer.
|
|
These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor. Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities (see next-but-one paragraph). However, complete in vitro transformation of normal human mesothelial cells to a malignant phenotype following exposure to asbestos fibers has not yet been achieved.
|
|
A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 has been identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects.
|
|
TERF2 as part of the shelterin complex, has been known to block the ATM signaling pathways and prevent chromosome end fusion. In cancer cells, TERF2 phosphorylation by extracellular signal-regulated kinase (ERK1/2) is a controlling factor in the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) that affect telomeric stability. Additionally, when TERF2 was non-phosphorylated in melanoma cells, there was a cell induced DNA damage response, arresting growth and causing tumor reversion. Studies have found that in tumor cells, TERF2 levels are observed to be high, and this raised level of TERF2 contributes to oncogenesis in a variety of ways.
|
|
Tyrosine-protein phosphatase non-receptor type 13 is an enzyme that in humans is encoded by the PTPN13 gene. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP is a large protein that possesses a PTP domain at C-terminus, and multiple noncatalytic domains, which include a domain with similarity to band 4.1 superfamily of cytoskeletal-associated proteins, a region consisting of five PDZ domains, and a leucine zipper motif.
|
|
In 1961, Rous sarcoma virus (RSV), which is closely related to ASLV, was shown to contain RNA, and oncogenic viruses, such as RSV and ASLV, were termed RNA tumor viruses. By the late 1960s, Howard Temin hypothesized that RSV made a copy of its own DNA and integrated that into the host cell's chromosomal DNA. Much debate in the scientific community surrounded this issue until DNA integration was demonstrated by Temin in 1968 and reverse transcriptase was independently discovered by both Temin and David Baltimore in 1970. Temin and Baltimore won the Nobel Prize in Medicine in 1975.
|
|
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.
|
|
ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in human prostate cancer, especially in hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. The fusion gene is critical to the progression of cancer because it inhibits the androgen receptor expression and it binds and inhibits androgen receptors already present in the cell. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue.
|
|
YAP1 is a transcriptional co-activator and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, which up-regulate genes that promote cell growth and inhibit apoptosis. Several other functional partners of YAP1 were identified, including RUNX, SMADs, p73, ErbB4, TP53BP, LATS1/2, PTPN14, AMOTs, and ZO1/2. YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway. When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins.
|
|
AML must be carefully differentiated from "preleukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently. Because acute promyelocytic leukemia (APL) has the highest curability and requires a unique form of treatment, it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose, as it readily identifies the chromosomal translocation [t(15;17)(q22;q12);] that characterizes APL. There is also a need to molecularly detect the presence of PML/RARA fusion protein, which is an oncogenic product of that translocation.
|
|
Lemmon's recent work has focused on the need to understand the biochemistry of oncogenic activation to use such drugs effectively. Before moving to Yale, Lemmon was George W. Raiziss Professor and Chair of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania. His research has been funded by the National Cancer Institute, the National Institute of General Medical Sciences, and the Department of Defense Congressionally Directed Medical Research Programs.Mark Lemmon's Lemmon serves on the editorial boards of several scientific journals, including Cell, Molecular Cell, Molecular and Cellular Biology, and Science Signaling.
|
|
CDK8 is a colorectal cancer oncogene: the CDK8 gene is amplified in human colorectal tumors, activating β-catenin-mediated transcription that drives colon tumorigenesis. However, CDK8 may not be oncogenic in all cell types, and indeed may act as a tumor suppressor in the notch and EGFR signaling pathways. Specifically, CDK8 promotes turnover of the notch intracellular domain, and inhibits EGFR signaling-driven cell fates in C. elegans. Thus, CDK8 may be an oncogene in cancers driven by Wnt/β-catenin signaling, but could instead be a tumor suppressor gene in cancers driven by notch or EGFR signaling.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic tyrosine phosphatase domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats, and thus is a member of the type R2B RPTP family.
|
|
SV40 large TAg, other polyomavirus large T antigens, adenovirus E1a proteins, and oncogenic human papillomavirus E7 proteins share a structural motif that encodes a high- affinity pRb-binding domain. This motif is characterized by an Asp, Asn or Thr residue followed by three invariant amino acids, interspersed with non- conserved amino acids (designated by x, where x cannot be a Lys or Arg residue). A negatively charged region frequently follows carboxy-terminal to the pRb-binding domain. : {Asp/Asn/Thr} – Leu – x – Cys – x – Glu – x – ... {negatively charged region} Hydrophobic and electrostatic properties are highly conserved in this motif.
|
|
The second most common malignant tumor in women is invasive cervical cancer (ICC) and more than 50% of all invasive cervical cancer (ICC) is caused by oncongenic human papillomavirus 16 (HPV16). Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16. As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Genomic methylation patterns have been associated with invasive cervical cancer. Within the HPV16L1 region, 14 tested CpG sites have significantly higher methylation in CIN3+ than in HPV16 genomes of women without CIN3.
|
|
MPyV is primarily spread among mice via the intranasal route and is shed in urine. Genetic susceptibility to MPyV infection among mice varies significantly, and not all MPyV strains are oncogenic. In general, only newborns and immunosuppressed mice (usually transgenic) develop tumors upon infection; although originally observed as a cause of parotid gland tumors, the virus may induce solid tumors in a wide variety of tissue types of both epithelial and mesenchymal origin. Although viruses in circulation among feral mice can be tumorigenic, under natural conditions the virus does not cause tumors; maternal antibodies have been shown to be critical in protecting neonates.
|
|
Historically, this substance has been best known for its involvement in plant-pathogen recognition, especially its role as a signal attracting and transforming unique, oncogenic bacteria in genus Agrobacterium. The virA gene on the Ti plasmid of Agrobacterium tumefaciens and the Ri plasmid of Agrobacterium rhizogenes is used by these soil bacteria to infect plants, via its encoding for a receptor for acetosyringone and other phenolic phytochemicals exuded by plant wounds. This compound also allows higher transformation efficiency in plants, as shown in A. tumefaciens-mediated transformation procedures, and so is of importance in plant biotechnology. Acetosyringone can also be found in Posidonia oceanica and a wide variety of other plants.
|
|
This work provided key insights into how both virus and cellular oncoproteins manipulate cellular physiology to bring about oncogenic transformation. One of his most significant achievements was the biochemical reconstitution with purified proteins of the complete replication of the SV40 DNA genome. This system utilized the virus-encoded T antigen that binds to the SV40 virus origin of DNA replication, the start site for DNA synthesis, coupled with purified human proteins, many of them discovered by Stillman and his colleagues. These proteins include RPA, RFC, PCNA, and the discovery that multiple DNA polymerases participate in the process of copying DNA, often switching from one polymerase to the other.
|
|
Cervical cancer is usually screened through in vitro examination of the cells of the cervix (e.g. Pap smear), colposcopy, or direct inspection of the cervix (after application of dilute acetic acid), or testing for HPV, the oncogenic virus that is the necessary cause of cervical cancer. Screening is recommended for women over 21 years, initially women between 21–29 years old are encouraged to receive Pap smear screens every three years, and those over 29 every five years. For women older than the age of 65 and with no history of cervical cancer or abnormality, and with an appropriate precedence of negative Pap test results may cease regular screening.
|
|
The role of PI-3-kinase in anabolic signaling by insulin, IGF-1, and other growth factors makes a straightforward link between metabolism and cancer, especially in light of the discovery that the PIK3CA gene encoding PI-3-kinase is an oncogene. In recent years Cantley and colleagues have made additional links between metabolic regulation and oncogenic transformation with their discovery that the M2 isoform of pyruvate kinase is associated with cancer. This discovery provides a molecular basis for understanding the Warburg effect. Cantley is now a major player in the resurgence of the importance of the Warburg effect in the process of oncogenesis.
|
|
From 1972, Moshé Yaniv decided to focus his research on the biology of oncogenic DNA viruses such as Polyome, SV40 and later on papilloma viruses in collaboration with Professor Gérard Orth. It highlights the chromatin structure of the viral genome and the absence of nucleosomes (histone octamers) on the sequences of expression regulation of viral and cellular genes.Saragosti S, et al., « Absence of nucleosomes in a fraction of SV40 chromatin between the origin of replication and the region coding for the late leader RNA. », Cell, 1980, p. 20:65Herbomel P, et al., « Two distinct enhancers with different cell specificities coexist in the regulatory region of polyoma. », Cell, 1984, p.
|
|
Tretinoin Mitozantrone Methotrexate APL is unique among leukemias due to its sensitivity to all-trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy.
|
|
Viral- mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington, Parkinson and Alzheimer diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes. TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease. TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of various oncogenic signals. Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2).
|
|
Acetosyringone has been best known for its involvement in plant-pathogen recognition,"Involvement of acetosyringone in plant-pathogen recognition". Baker C. Jacyn, Mock Norton M., Whitaker Bruce D., Roberts Daniel P., Rice Clifford P., Deahl Kenneth L. and Aver'Yanov Andrey A., Biochemical and Biophysical Research Communications, 2005, volume 328, number 1, pp. 130–136, especially its role as a signal attracting and transforming unique, oncogenic bacteria in genus Agrobacterium. The virA gene on the Ti plasmid in the genome of Agrobacterium tumefaciens and Agrobacterium rhizogenes is used by these soil bacteria to infect plants, via its encoding for a receptor for acetosyringone and other phenolic phytochemicals exuded by plant wounds.
|
|
Young has made major contributions to the understanding of gene control in human development and disease. He discovered that a small set of human embryonic stem cell master transcription factors form a core regulatory circuitry that controls the gene expression program of these cells. This concept of core regulatory circuitry helps guide current efforts to understand gene control, to develop reprogramming protocols for other human cell types and to understand how gene dysregulation contributes to disease. Young has introduced the concept of transcriptional amplification and described how much of the gene control program in cancer cells is amplified by oncogenic transcription factors such as c-MYC.
|
|
Cleft lip and palate transmembrane protein 1-like protein (CLPTM1-like protein), also known as cisplatin resistance-related protein 9 (CRR9p), is a protein that in humans is encoded by the CLPTM1L gene. CRR9p is associated with cisplatin-induced apoptosis. CLPTM1L, which lies within a cancer susceptibility locus on chromosome 5 (5p15.33), has been found to be commonly over-expressed in lung tumors and to confer resistance to apoptosis caused by genotoxic agents in association with up-regulation of the anti-apoptotic protein, Bcl-xL. Inhibition of CLPTM1L has been shown to inhibit oncogenic transformation and tumorigenesis caused by the KRas oncogene partially through the PI3K/Akt survival signaling axis.
|
|
For example, those released from antigen- presenting cells (APCs), such as B cells and dendritic cells, are enriched in proteins necessary for adaptive immunity, while microvesicles released from tumors contain proapoptotic molecules and oncogenic receptors (e.g. EGFR). In addition to the proteins specific to the cell type of origin, some proteins are common to most microvesicles. For example, nearly all contain the cytoplasmic proteins tubulin, actin and actin-binding proteins, as well as many proteins involved in signal transduction, cell structure and motility, and transcription. Most microvesicles contain the so-called "heat-shock proteins" hsp70 and hsp90, which can facilitate interactions with cells of the immune system.
|
|
It has been known for 30 years that the corresponding gene fusion plays an important role in tumorgenesis. Fusion genes can contribute to tumor formation because fusion genes can produce much more active abnormal protein than non-fusion genes. Often, fusion genes are oncogenes that cause cancer; these include BCR-ABL, TEL-AML1 (ALL with t(12 ; 21)), AML1-ETO (M2 AML with t(8 ; 21)), and TMPRSS2-ERG with an interstitial deletion on chromosome 21, often occurring in prostate cancer. In the case of TMPRSS2-ERG, by disrupting androgen receptor (AR) signaling and inhibiting AR expression by oncogenic ETS transcription factor, the fusion product regulates the prostate cancer.
|
|
The underlying molecular mechanism of this anti-tumor effect was found to be by the specific inhibition of activity of oncogenic BRAFV600E in tumors that harbored the mutation. However, in tumors that expressed wild type BRAF, Indole-3-carbinol did not cause any comparable antiproliferative effect. Additionally Indole-3-carbinol did not cause antiproliferation even in normal epidermal melanocytes underscoring the specificity and selectivity of its action. Kundu et al further showed that inhibition of BRAF V600E activity by Indole-3-carbinol resulted in downregulation of MITF-M by downstream signaling which caused a G1 cell cycle arrest leading to the observed antiproliferative effect.
|
|
Chakadar and al. found significant synergistic stimulation of the GAST gene promoter (by a factor of 25-40) by a combination of oncogenic ß-catenin and K-Ras overexpression. Activation of the GAST gene promoter was also shown to be dependent on other signalling signals: enhanced or suppressed by co-expression of wild-type SMAD4 or by a dominant negative mutant of SMAD4, respectively, and abrogated by inhibition of PI3K. Thus, constitutive activation of the Wnt pathway, considered to be at the onset of tumorigenesis in the colon, and the K-Ras oncogene, present in 50% of human colorectal tumors, synergistically stimulate the production of hPG80, a tumorigenesis promoter.
|
|
The presence of AU-rich elements in some mammalian mRNAs tends to destabilize those transcripts through the action of cellular proteins that bind these sequences and stimulate poly(A) tail removal. Loss of the poly(A) tail is thought to promote mRNA degradation by facilitating attack by both the exosome complex and the decapping complex. Rapid mRNA degradation via AU-rich elements is a critical mechanism for preventing the overproduction of potent cytokines such as tumor necrosis factor (TNF) and granulocyte-macrophage colony stimulating factor (GM-CSF). AU-rich elements also regulate the biosynthesis of proto-oncogenic transcription factors like c-Jun and c-Fos.
|
|
No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when expressed by a retrovirus. Trial treatments of SCID have been gene therapy's first success; since 1999, gene therapy has restored the immune systems of at least 17 children with two forms (ADA-SCID and X-SCID) of the disorder. There are also some non-curative methods for treating SCID. Reverse isolation involves the use of laminar air flow and mechanical barriers (to avoid physical contact with others) to isolate the patient from any harmful pathogens present in the external environment.
|
|
The expression of DUSP1 gene is induced in human skin fibroblasts by oxidative/heat stress and growth factors. It specifies a protein with structural features similar to members of the non- receptor-type protein-tyrosine phosphatase family, and which has significant amino-acid sequence similarity to a Tyr/Ser-protein phosphatase encoded by the late gene H1 of vaccinia virus. The bacterially expressed and purified DUSP1 protein has intrinsic phosphatase activity, and specifically inactivates mitogen-activated protein (MAP) kinase in vitro by the concomitant dephosphorylation of both its phosphothreonine and phosphotyrosine residues. Furthermore, it suppresses the activation of MAP kinase by oncogenic ras in extracts of Xenopus oocytes.
|
|
By extension of this fact, Skp2 inactivation profoundly restricts cancer development by triggering a massive cellular senescence and/or apoptosis response that is surprisingly observed only in oncogenic conditions in vivo. This response is triggered in a p19Arf/p53-independent, but p27-dependent manner. Using a Skp2 knockout mouse model, multiple groups have shown Skp2 is required for cancer development in different conditions of tumor promotion, including PTEN, ARF, pRB in activation as well as Her2/Neu overexpression. Genetic approaches have demonstrated that Skp2 deficiency inhibits cancer development in multiple mouse models by inducing p53-independent cellular senescence and blocking Akt- mediated aerobic glycolysis.
|
|
One possible way to achieve this, which has been successful in mouse models, is to use inhibitors of Ras activation in order to enhance the functionality of these adhesion systems. Other catenin, cadherin or cell cycle regulators may also be useful in treating a variety of cancers. While recent studies in the lab and in the clinic have provided promising results for treating various catenin-associated cancers, the Wnt/β-catenin pathway may make finding a single correct therapeutic target difficult as the pathway has been shown to elicit a variety of different actions and functions, some of which may possibly even prove to be anti-oncogenic.
|
|
Ze’ev Ronai studies provide new fundamental understanding for the role and function of epigenetic components (transcription factor and ubiquitin ligases) in cancer. Early in his career he developed a sensitive PCR approach to detect mutant Ras oncogene in normal appearing tissues. Later on, his studies provided the foundation for the rewired signaling in cancer, by demonstrating the important role of protein subcellular localization in its oncogenic function and by establishing the function of ubiquitin ligases in key cellular processes (i.e. hypoxia, unfolded protein response, mitochondrial dynamics, anti-tumor immunity) and their critical contribution to development, progression, and therapy resistance of prostate and breast cancers and melanoma.
|
|
He was the first to fully clone the focal adhesion protein paxillin (human and chicken) and demonstrate its role in oncogenic transformation. As an independent clinician- scientist, Salgia's major research interests include elucidating how the receptor tyrosine kinases affect cell growth, and understanding tumor heterogeneity, including the role of cell-signaling pathways, mitochondria, immunology, and mathematical modeling Salgia was born in Indore, Madhya Pradesh, India. He earned his undergraduate degree summa cum laude in mathematics, biology, and chemistry, minor in physics and then his medical degree and Ph.D. in biochemistry and biophysics from Loyola University of Chicago. There he also completed a fellowship in neurochemistry and physiology.
|
|
The mature microRNA products are thought to regulate expression levels of other genes through complementarity to the 3' UTR of specific target messenger RNA. The paralogous miRNA gene clusters that give rise to miR-17 family microRNAs (miR-17~92, miR-106a~363, and miR-106b~25) have been implicated in a wide variety of malignancies and are sometimes referred to as oncomirs. The oncogenic potential of these non-protein encoding genes was first identified in mouse viral tumorigenesis screens. In humans, the activating mutations of miR-17~92 have been identified in non-Hodgkin's lymphoma, whereas the miRNA constituents of the clusters are overexpressed in a multiple cancer types.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region containing five fibronectin type III repeats, a single transmembrane region, and a single intracytoplasmic catalytic domain, and thus represents a receptor-type PTP. This PTP is present in all hematopoietic lineages, and was shown to negatively regulate T cell receptor signaling possibly through interfering with the phosphorylation of Phospholipase C Gamma 1 (PLCG1) and Linker for Activation of T Cells (LAT).
|
|
Additionally, YAP is regulated by mechanical cues such as extracellular matrix (ECM) rigidity, strain, shear stress, or adhesive area, processes that are reliant on cytoskeletal integrity. These mechanically induced localization phenomena are thought to be the result of nuclear flattening induced pore size change, mechanosensitive nuclear membrane ion channels, mechanical protein stability, or a variety of other factors. These mechanical factors have also been linked to certain cancer cells via nuclear softening and higher ECM stiffnesses. Under this framework, the nuclear softening phenotype of cancer cells would promote nuclear flattening in response to a force, causing YAP localization, which could explain its over- expression and promoted proliferation in oncogenic cells.
|
|
T-DNA contains two types of genes: the oncogenic genes, encoding for enzymes involved in the synthesis of auxins and cytokinins and responsible for tumor formation; and the genes encoding for the synthesis of opines. These compounds, produced by condensation between amino acids and sugars, are synthesized and excreted by the crown gall cells and consumed by A. tumefaciens as carbon and nitrogen sources. Outside the T-DNA, are located the genes for the opine catabolism, the genes involved in the process of T-DNA transfer from the bacterium to the plant cell and the genes involved in bacterium-bacterium plasmid conjugative transfer. (Hooykaas and Schilperoort, 1992; Zupan and Zambrysky, 1995).
|
|
MAS proto-oncogene, or MAS1 proto-oncogene, G protein-coupled receptor (MRGA,MAS,MGRA""), is a protein that in humans is encoded by the MAS1 gene. The structure of the MAS1 product indicates that it belongs to the class of receptors that are coupled to GTP-binding proteins and share a conserved structural motif, which is described as a '7-transmembrane segment' following the prediction that these hydrophobic segments form membrane-spanning alpha- helices. The MAS1 protein may be a receptor that, when activated, modulates a critical component in a growth-regulating pathway to bring about oncogenic effects. Agonists of the receptor include angiotensin-(1-7).
|
|
Knocking down ARF with siRNA to exon 1β results in increased rRNA transcripts, rRNA processing, and ribosome nuclear export. The unrestrained ribosome biogenesis seen when NPM is not bound to ARF does not occur if NPM is also absent. Although the induction of ARF in response to oncogenic signals is considered to be of primary importance, the low levels of ARF seen in interphase cells also has a considerable effect in terms of keeping cell growth in check. Therefore, the function of basal level ARF in the NPM/ARF complex appears to be to monitor steady-state ribosome biogenesis and growth independently of preventing proliferation.
|
|
In many cases, risk factors for precancerous conditions and lesions are the same risk factors that predispose individuals to a specific cancer. For example, individuals with cervical or anal infection with oncogenic, or cancer causing, strains of human papilloma virus (HPV) are at elevated risk for cervical and anal cancers, respectively, as well as for cervical and anal dysplasia. Similarly, sun exposure is an important risk factor for both actinic keratosis as well as skin cancer. However, in many cases, precancerous conditions or lesions can be sporadic and idiopathic in nature, meaning that they are not associated with a hereditary genetic predisposition to the particular cancer, nor with a direct causative agent or other identifiable cause.
|
|
Close-up view of an actinic keratosis lesion Multiple lesions of actinic keratosis on the scalp. Actinic keratoses (AKs) most commonly present as a white, scaly plaque of variable thickness with surrounding redness; they are most notable for having a sandpaper-like texture when felt with a gloved hand. Skin nearby the lesion often shows evidence of solar damage characterized by notable pigmentary alterations, being yellow or pale in color with areas of hyperpigmentation; deep wrinkles, coarse texture, purpura and ecchymoses, dry skin, and scattered telangiectasias are also characteristic. Photoaging leads to an accumulation of oncogenic changes, resulting in a proliferation of mutated keratinocytes that can manifest as AKs or other neoplastic growths.
|
|
The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands) and diffuse large B-cell lymphoma. Lymphomagenesis in primary SS patients is considered as a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that produce rheumatoid factor at sites targeted by the disease. This increases the frequency of oncogenic mutation, leading to any dysfunction at checkpoints of autoimmune B-cell activation to transform into malignancy. A study's finding has concluded the continuous stimulation of autoimmune B cells, leading to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.
|
|
Evidence for a fibroblast precursor includes its location in the dermis, which is thought to be the primary site of origin for MCC. Additionally, in vitro experiments have demonstrated that fibroblasts not only support MCV infection but can be induced into having a MCC phenotype by the expression of viral proteins. However, others have argued that MCC likely derives from an epithelial precursor cell due to its frequent presence in mixed tumors including epithelial neoplasms such as squamous cell carcinoma. While epithelial cells are not typically found in the dermis, hair follicles include epithelial cells that have been shown to have oncogenic potential, and have therefore been proposed as a possible site for a MCC precursor.
|
|
The International Cancer Genome Consortium (ICGC) is a voluntary scientific organization that provides a forum for collaboration among the world's leading cancer and genomic researchers. The ICGC was launched in 2008 to coordinate large-scale cancer genome studies in tumours from 50 cancer types and/or subtypes that are of main importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies. The ICGC incorporates data from The Cancer Genome Atlas (TCGA) and the Sanger Cancer Genome Project.
|
|
For example, it has been shown that vFLIP and vCyclin interfere with the TGF-β signaling pathway indirectly by inducing oncogenic host mir17-92 cluster. Indirect viral oncogenicity involves chronic nonspecific inflammation occurring over decades of infection, as is the case for HCV-induced liver cancer. These two mechanisms differ in their biology and epidemiology: direct tumor viruses must have at least one virus copy in every tumor cell expressing at least one protein or RNA that is causing the cell to become cancerous. Because foreign virus antigens are expressed in these tumors, persons who are immunosuppressed such as AIDS or transplant patients are at higher risk for these types of cancers.
|
|
The stabilization of oncogenic K-Ras by APC loss and subsequent re-activation the Wnt/beta-catenin pathway via positive loop through ERK activated cancer stem cells and induced liver metastasis of colorectal cancer. This indicates the importance of inhibition of both Wnt/beta-catenin and Ras-ERK pathways in the treatment of colorectal cancer. He subsequently identified and characterized small molecules degrading both beta-catanin and Ras via targeting the Wnt/beta-catenin signaling, and those small molecules efficiently inhibit growth of colorectal and other cancers with activated Wnt/beta-catenin and EGFR-Ras pathways. He served as the Chief of the National Research Laboratory of the Molecular Complex Control in Yonsei University for recent 5 years.
|
|
Downward's research investigates cancer biology. His work on the Ras GTPase has made seminal contributions to our understanding of how cellular signal transduction pathways are subverted in oncogenic transformation. His work provided the first demonstration that Guanosine triphosphate-loading on Ras, which is commonly mutationally activated in human tumours, is normally regulated in response to extracellular factors; he went on to characterise growth factor receptor complexes mediating Ras nucleotide exchange, and to demonstrate that GTP-bound Ras binds to and activates the RAF kinase, which controls the mitogen-activated protein kinase pathway. Julian was first to demonstrate that phosphoinositide 3-kinase (PI 3-kinase) is also a Ras effector, important in regulation of apoptosis.
|
|
IRS-1, as a signalling adapter protein, is able to integrate different signalling cascades, which indicates its possible role in cancer progression. IRS-1 protein is known to be involved in various types of cancer, including colorectal, lung, prostate and breast cancer. IRS-1 integrates signalling from insulin receptor (InsR), insulin-like growth factor-1 receptor (IGF1R) and many other cytokine receptors and is elevated in β-catenin induced cells. Some evidence shows that TCF/LEF-β-catenin complexes directly regulate IRS-1. IRS-1 is required for maintenance of neoplasmic phenotype in adenomatous polyposis coli (APC) - mutated cells, it is also needed for transformation in ectopically expressing oncogenic β-catenin cells.
|
|
Cells containing oncogenic mutations in-vivo often responded by activating the INK4A/ARF/INK4B locus that encodes the INK4 tumor suppressor proteins. The unusual genomic arrangement of the INK4a/ARF/INK4b locus functions as a weakness in our anti-cancer defenses. This is due to the fact that three crucial regulators of the RB and p53 (regulated by ARF) are vulnerable to one single, small deletion. This observation yields two possible opposing conclusions: Either tumor formation does not provide any evolutionary selection pressure because the overlapping INK4a/ARF/INK4b is not selected against or tumorigenesis provides such a strong pressure, that an entire group of genes has been selected for at the INK4a/ARF/INK4b locus to prevent cancer.
|
|
They form a classic group for the study of medullablastoma and other cancers and include mice lines that are KO for p53, Ptch1, and Ink4c. Of the 26 miRNAs showing higher expression levels (in one of the mutant groups) against wild type mice, 9 of them were from the mir-17-92 cluster and its 2 paralogs. Overall signature changes across mutant groups and control groups were largely insignificant and the mir-17-92 cluster was only implicated in mutant mice that had an active SHH pathway. These observations merited further focus on the cluster and QRT-PCR was used to measure the expression of the oncogenic cluster in samples of MB tumours more accurately.
|
|
In many kinds of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities. The most common known aberrations include the PIK3CA gene mutation and the loss-of-function mutations or epigenetic silencing of phosphatase and tensin homologue (PTEN). The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is activated in approximately 30–40% of BC cases. In TNBC, oncogenic activation of the PI3K/AKT/mTOR pathway can happen as a function of overexpression of upstream regulators like EGFR, activating mutations of PIK3CA, loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K.
|
|
The symbol ABL1 is derived from Abelson, the name of a leukemia virus which carries a similar protein. The symbol BCR is derived from breakpoint cluster region, a gene which encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins Translocation results in an oncogenic BCR-ABL1 gene fusion that can be found on the shorter derivative chromosome 22. This gene encodes for a BCR-ABL1 fusion protein. Depending on the precise location of fusion, the molecular weight of this protein can range from 185 to 210 kDa. Consequently, the hybrid BCR-ABL1 fusion protein is referred to as p210 or p185. Three clinically important variants encoded by the fusion gene are the p190, p210, and p230 isoforms.
|
|
Aubrey de Grey, a leading researcher in the field, defines aging as "a collection of cumulative changes to the molecular and cellular structure of an adult organism, which result in essential metabolic processes, but which also, once they progress far enough, increasingly disrupt metabolism, resulting in pathology and death." The current causes of aging in humans are cell loss (without replacement), DNA damage, oncogenic nuclear mutations and epimutations, cell senescence, mitochondrial mutations, lysosomal aggregates, extracellular aggregates, random extracellular cross-linking, immune system decline, and endocrine changes. Eliminating aging would require finding a solution to each of these causes, a program de Grey calls engineered negligible senescence. There is also a huge body of knowledge indicating that change is characterized by the loss of molecular fidelity.
|
|
In 2006, Daiichi Sankyo acquired Zepharma, the OTC drugs unit of Astellas Pharma. On June 10, 2008, Daiichi Sankyo agreed to take a majority (64%) stake in Indian generic drug maker Ranbaxy, with a deal valued at about $4.6 billion. In June 2008, Daiichi Sankyo acquired U3 Pharma, which would contribute a therapeutic anti-HER3 antibody to the company's anticancer portfolio. On April 4, 2011 Daiichi Sankyo completed the acquisition of Plexxikon, a Berkeley, California-based pharmaceutical start-up company for $805 million and an additional $130 million in milestone payments, pending on the success of Vemurafenib (Plexxikon's lead program) an oral, novel drug that targets the oncogenic BRAF mutation present in about half of melanoma cancers and about eight percent of all solid tumors.
|
|
In tumorigenesis, IL-17A has been shown to recruit myeloid derived suppressor cells (MDSCs) to dampen anti-tumor immunity. IL-17A can also enhance tumor growth in vivo through the induction of IL-6, which in turn activates oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) and upregulates pro- survival and pro-angiogenic genes in tumors. The exact role of IL-17A in angiogenesis has yet to be determined and current data suggest that IL-17A can promote or suppress tumor development. IL-17A seemed to facilitate development of colorectal carcinoma by fostering angiogenesis via promote VEGF production from cancer cells and it has been show that IL-17A also mediates tumor resistance to anti-VEGF therapy through the recruitment of MDSCs.
|
|
In neuronal tissue, STIM2 plays a crucial role in ischemia-induced neuronal damage, and the absence of STIM2 in knockout mice reduced the neuronal damage produced by ischemia after transient interruption of blood flow in brain. This neuroprotective effect of STIM2-deficiency after an ischemic episode indicates that inhibitors of STIM2 function may thus have a potential therapeutic value as neuroprotective agents to treat ischemic injury and other neurodegenerative disorders involving altered Ca2+ homeostasis. Moreover, the same scientific study suggested an important role of STIM2 in hippocampus-dependent spatial memory, synaptic transmission and plasticity. Finally, an oncogenic function has been demonstrated for STIM2, together with STIM1, in glioblastoma multiforme, where both proteins have increased expression and/or increased copy number.
|
|
Allis discovered the critical link, through histone acetyltransferase-containing transcriptional coactivators, between targeted histone acetylation and gene- specific transcriptional activation. In further studies, he linked histone phosphorylation events to mitosis and mitogen action, established a synergy between histone phosphorylation and acetylation events and elaborated the ‘histone code hypothesis’ (and extensions thereof), one of the most highly cited theories governing epigenetics. Recent studies suggest a new model wherein histone mutations (‘oncohistones’) represent a novel and previously unrecognized mechanism to alter epigenetic states in a variety of pathologies through inhibition of a wide range of histone methyltransferases. In turn, oncohistone mutations exert their oncogenic effect by reprogramming the cellular epigenome and transcriptome, thereby disrupting the highly coordinated epigenetic programs required for cell-specific differentiation.
|
|
Subsequently, oncogenic bacterial strains were found to be able to convert non-pathogenic bacteria into pathogens via the process of conjugation, where the genes responsible for virulence were transferred to the non-pathogenic cells. The role of a plasmid in this pathogenic ability was further supported when large plasmids were found only in pathogenic bacteria but not avirulent bacteria. Eventually, the detection of parts of bacterial plasmids in host plant cells was established, confirming that this was the genetic material responsible for the genetic effect of infection. With the identification of the Ti plasmid, many studies were carried out to determine the characteristics of the Ti plasmid and how the genetic material is transferred from the Agrobacterium to the plant host.
|
|
The Gag-v-Onc fusion protein from the Rous sarcoma virus illustrates the dual role that the fusion protein plays in the viral and host cellular life cycle. For example, the viral gene Src (as in "sarcoma") is not necessary for viral reproduction, but does affect virulence. Due to evidence of conserved homology between the v-Src gene and its host (animal) genomes, and its non-essential status for viral reproduction, the v-Src gene is likely to have been acquired from a host genome and altered by subsequent mutations. These subsequent mutations are responsible for the oncogenic capabilities of the virus, as the normal (host) version of the Src gene, c-Src promotes survival, angiogenesis, proliferation and invasion pathways.
|
|
Building on their work and taking notice of the work of Henry G. Kunkel, whose group made the association of higher levels of circulating DNA and lupus, Stroun started studying whether circulating DNA could be associated with malignancies such as cancers in humans. In a 1977 issue of International Review of Cytology, Volume 51, Anker and Stroun wrote that when foreign DNA is transcribed into a cell of a different organism, "this general biological event is related to the uptake by cells of spontaneously released bacterial DNA, thus suggesting the existence of circulating DNA. In view of the malignant transformations obtained with DNA, the oncogenic (cancer-causing) role of circulating DNA is postulated."1977 issue of International Review of Cytology, Volume 51, Anker and Stroun.
|
|
The work of Williams group is deciphering mechanisms of activation and inhibition of diverse members of the phosphoinositide 3-kinase (PI3K) enzyme a family of enzymes involved in cell-cell communication, lysosomal sorting, nutrient sensing, cell proliferation and DNA-damage response. Mutations in PI3K signalling pathways are common in human tumours, and the William lab focuses on how they contribute to oncogenesis and how pharmaceuticals can specifically target these pathways. The Williams group has shown how conformational changes in the p110 alpha isoform accompanies its activation on cell membranes, and established that oncogenic mutations activate PI3Ks by mimicking or enhancing these conformational changes. His group is uncovering structural and dynamic features that dictate the extreme sensitivity of PI3K complexes to membrane lipid packing and membrane curvature.
|
|
Mice with mutations in transforming growth factor-β1 gene introduced into 129/Sv Rag2 mutant mouse accelerates adenocarcinomas with strong local invasion suggesting a role for genetic background in tumor development. Colon- specific expression of activated mutant of K-ras (protein) (K-rasG12D) results in development of single or multiple lesions. Oncogenic K-rasG12D allele activated in colon epithelium induces expression of procarcinogenic protein kinase C-βII (PKCβII) and increases cell proliferation of epithelial cells, while in the distal colon the mutant form of K-ras has the opposite effects on PKCβII expression and cell proliferation. Treatment of this mouse model with the procarcinogen azoxymethane (AOM) leads to formation of dysplastic microadenomas in the proximal but not in the distal colon.
|
|
Several classes of MAPKKK exist, and all of them are upstream of MAP kinases. There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs. These MAP kinases include the extracellular regulated kinases (ERKs), the c-Jun N-terminal Kinases (JNKs), and the p38 MAP kinase. The ERKs are regulated by the Raf family of MAPKKKs and are responsible for cell growth, differentiation, and meiosis. Perhaps the best characterized MAP3K are the members of the oncogenic RAF family (RAF1, BRAF, ARAF), which are effectors of mitogenic ras signaling and which activate the ERK1/2 (MAPK3/MAPK1) pathway, through activation of MEK1(MAP2K1) and MEK2(MAP2K2). The JNKs are regulated by the MEKK 1/4, MLK 2/3, and ASK 1 MAPKKKs.
|
|
As a consequence, AML-ETO retains the ability to bind at RUNX1 target genes whilst acting as a transcription repressor via the recruitment of corepressors and histone deacetylases, which is an intrinsic function of ETO. Oncogenic potential of AML-ETO is exerted because it blocks differentiation and promote self-renewal in blast cells, resulting in massive accumulation of blasts (>20%) in the bone marrow. This is further characterized histologically by the presence of Auer rods and epigenetically by lysine acetylation on residues 24 and 43. Other actions of AML-ETO that could induce leukemogenesis include downregulation of the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) and increase in the level of intracellular reactive oxygen species, making cells that express AML- ETO more susceptible to additional genetic mutations.
|
|
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Two alternatively spliced transcript variants of this gene have been reported, one of which encodes a receptor-type PTP that possesses a short extracellular domain, a single transmembrane region, and two tandem intracytoplasmic catalytic domains; Another one encodes a PTP that contains a distinct hydrophilic N-terminus, and thus represents a nonreceptor-type isoform of this PTP. Studies of the similar gene in mice suggested the regulatory roles of this PTP in RAS related signal transduction pathways, cytokines induced SATA signaling, as well as the activation of voltage-gated K+ channels.
|
|
In some tumours, (the cancerous state), some receptor tyrosine kinases tend to be over-active, due to genetic changes. Ullrich is also Principal Investigator of Singapore Oncogenome Project at the Institute of Medical Biology aimed at identifying all oncogenic alterations in all protein tyrosine kinase (PTK) gene transcripts of a large number of tumor cell lines and primary tumors. The laboratory also focuses on functional characterization and, in cooperation with clinical oncologists, investigation of the clinical relevance of the newly discovered PTK oncogenes which serves as basis for the development of novel multi-targeted drugs. The discovery of the drug Sunitinib and clarification of the multi-specific mechanism of action is partly based on discoveries of Axel Ullrich and his team at the Max Planck Institute of Biochemistry in the 1980s in Munich.
|
|
HPV is a virus, usually transmitted sexually, which can cause cervical cancer in a small percentage of those women genital infected. Cervarix is a preventative HPV vaccine, not therapeutic. HPV immunity is type-specific, so a successful series of Cervarix shots will not block infection from cervical cancer-causing HPV types other than HPV types 16 and 18 and some related types, so experts continue to recommend routine cervical Pap smears even for women who have been vaccinated. Vaccination alone, without continued screening, would prevent fewer cervical cancers than regular screening alone. Cervarix is indicated for the prevention of the following diseases caused by oncogenic HPV types 16 and 18: cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and CIN grade 1.
|
|
Human breast cancer often expresses and appears promoted by Ras proteins (see carcinogenesis and the Ras subfamily). The forced expression of oncogenic Ras in cultured human MCF-10A breast cancer cells markedly up- regulates BLT2 receptors and this up-regulation appears essential for the epithelial–mesenchymal transition-promoting ability of Transforming growth factor beta in these cells; BLT2 receptors in these cells appear to stimulate the production of reactive oxygen species and activation of NF-κB and may thereby contribute to the metastatic ability of breast cancer. Since BLT2 receptors are significantly elevated in human breast cancer tissue compared to non-cancerous breast tissue, the cited studies, when taken together, indicate that BLT2 receptors promote the malignant growth, invasiveness, metastasis and possibly anti-cancer drug resistance of not only cultured human breast cancer cells but also of human breast cancer.
|
|
Harald zur Hausen went against current dogma and postulated that oncogenic human papilloma virus (HPV) caused cervical cancer. He realized that HPV-DNA could exist in a non-productive state in the tumours, and should be detectable by specific searches for viral DNA. He and others, notably workers at the Pasteur Institute, found HPV to be a heterogeneous family of viruses. Only some HPV types cause cancer. Harald zur Hausen pursued his idea of HPV for over 10 years by searching for different HPV types. [3] This research was difficult due to the fact that only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in 1983. In 1984, he cloned HPV16 and 18 from patients with cervical cancer.
|
|
The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world. His observation of HPV oncogenic potential in human malignancy provided impetus within the research community to characterize the natural history of HPV infection, and to develop a better understanding of mechanisms of HPV- induced carcinogenesis. In December 2014, the United States' Food and Drug Administration (FDA) approved a vaccine called Gardasil 9 to protect females between the ages of 9 and 26 and males between the ages of 9 and 15 against nine strains of HPV. Gardasil 9 protects against infection with the strains covered by the first generation of Gardasil (HPV-6, HPV-11, HPV-16, and HPV-18) and protects against five other HPV strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58).
|
|
Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431, that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B. In addition, PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates. In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases.
|
|
RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene on human chromosome 22, specifically 22q12.2. This region of chromosome 22 encodes the N-terminal transactivation domain of the EWS protein and that region may become joined to one of several other chromosomes which encode various transcription factors, see The expression of a chimeric protein with the EWS transactivation domain fused to the DNA binding region of a transcription factor generates a powerful oncogenic protein causing Ewing sarcoma and other members of the Ewing family of tumors. These translocations can occur due to chromoplexy, a burst of complex chromosomal rearrangements seen in cancer cells. The normal EWS gene encodes a RNA binding protein closely related to FUS (gene) and TAF15, all of which have been associated to amyotrophic lateral sclerosis.
|
|
In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a mouse-tropic strain of Murine leukemia virus isolated from the brain of a mouse captured at Lake Casitas, California known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from a mouse into which it was injected. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumor formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.
|
|
Thompson holds more than 30 patents related to immunotherapy and apoptosis, and is a founder of three biotechnology companies. Patents arising from Thompson’s research describing the co-stimulatory/inhibitory properties of CD28/CTLA-4, in collaboration with Carl June and Jeffrey Bluestone, were licensed for the development of Abatacept (Orencia) for autoimmune diseases and for use in T cell cloning and CAR T cell production. Thompson’s work with Stanley Korsmeyer establishing the existence of three classes of Bcl-2-related proteins and defining their role in apoptosis led to the development of ABT-263 (navitoclax) and ABT-199 (venetoclax), recently FDA-approved for certain patients with chronic lymphocytic leukemia (CLL). Thompson’s discovery of oncogenic metabolites (succinate, fumarate, and 2-hydroxyglutarate) that can inhibit tumor suppressor function and/or impair cellular differentiation has helped lead to the development of new treatments for leukemia, gliomas, sarcomas, and bladder cancer, currently in clinical trials.
|
|
Dalldorf also collaborated with Gifford on many early papers. The coxsackieviruses subsequently were found to cause a variety of infections, including epidemic pleurodynia (Bornholm disease), and were subdivided into groups A and B based on their pathology in newborn mice. (Coxsackie A virus causes paralysis and death of the mice, with extensive skeletal muscle necrosis; Coxsackie B causes less severe infection in the mice, but with damage to more organ systems, such as heart, brain, liver, pancreas, and skeletal muscles.) The use of suckling mice was not Dalldorf's idea but was brought to his attention in a paper written by Danish scientists Orskov and Andersen in 1947, who were using such mice to study a mouse virus. The discovery of the coxsackieviruses stimulated many virologists to use this system, and ultimately resulted in the isolation of a large number of so- called "enteric" viruses from the gastrointestinal tract that were unrelated to poliovirus, and some of which were oncogenic (cancer-causing).
|
|
The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes, and developmentally important genes such as the polycomb group of genes. The BARD1 protein also contains three tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. BARD1 may be the target of oncogenic mutations in breast or ovarian cancer. Mutations in the BARD1 protein that affect its structure appear in many breast, ovarian, and uterine cancers, suggesting the mutations disable BARD1's tumor suppressor function. Three missense mutations, each affecting BARD1's BRCT domain, are known to be implicated in cancers: C645R is associated with breast and ovarian cancers, V695L is associated with breast cancer, and S761N is associated with breast and uterine cancers.
|
|
Although uncommonly used in North America and northern Europe, this test correlates better with disease status and predicts relapse more accurately than any other test. Hairy cells respond to normal production of some cytokines by T cells with increased growth. Treatment with Interferon-alpha suppresses the production of this pro-growth cytokine from T cells. A low level of T cells, which is commonly seen after treatment with cladribine or pentostatin, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells. In June 2011, E Tiacci et alResearch on hairy-cell leukaemia shows the promise of new DNA-scanning technologies - Cancer Research UK science blog discovered that 100% of hairy- cell leukaemia samples analysed had the oncogenic BRAF mutation V600E, and proposed that this is the disease's driver mutation. Until this point, only a few genomic imbalances had been found in the hairy cells, such as trisomy 5 had been found.
|
|
Lutz Gissmann (born Sept 18, 1949 in Kaufbeuren, Germany) is a German virologist and was head of the Division “Genome Modifications and Carcinogenesis” at the German Cancer Research Center (DKFZ) in Heidelberg until his retirement in 2015. Lutz Gissmann is known for his seminal research in the field of human papillomaviruses (HPV) and their causal association with human cancer, especially cervical cancer. In his early work, he demonstrated genetic heterogeneity among HPV isolates leading the way to the now well- established concept of distinct HPV types (up to now more than 200) of which some are associated with specific benign or malignant disease. In the early 1980s in the laboratory of later Nobel Prize laureate Harald zur Hausen he was the first (together with the postgraduates Matthias Dürst and Michael Boshart supervised by him) to isolate and characterize HPV16 and HPV18, the two most oncogenic HPV types causing the vast majority of HPV-induced anogenital and head-and-neck cancers.
|
|
To study the functions of microRNA, a detailed protocol of bacmid mutagenesis and a complete set of cell-lines carrying microRNA deletion mutants have been established by leading researchers in the field, that are available as a resource to any international researcher working in field of virus-associated cancer. Additionally, in another study, it has been shown that vFLIP and vCyclin interfere with the TGF-β signaling pathway indirectly by inducing oncogenic host mir17-92 cluster. These observations represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. The development of crucial tools such as complete set of 12 microRNA deletion mutants are important development in studying the functions of KLAR gene in context of KSHV associated tumorigenesis Crucial for the Entry of the KSHV is the EPH receptor A2, Hrs, TSG101 and a few Integrins, whose identity has yet to be confirmed. The virus exists as a circular piece of DNA called an episome and uses the cellular replication machinery to replicate itself.
|
|
The lesions in ITCLD-GT consists of slowly growing, mature, and benign-appearing T cells. The reasons for their accumulations in the GI tract are unclear. However, these cells often carry potentially oncogenic mutations. In a recent study, the T cells in 4 of 5 patients with CD4+ T-cell disease carried a STAT3-JAK2 fusion gene. This gene consists of a fusion between the STAT3 gene at position 2.2 on the long (or "g") arm of chromosome 17 (location abbreviated 17q21.2) and the JAK2 gene at position 24.1 on the short ("q") of chromosome 9 (9p24.1). The disorder in two of the patients with this t(9;17)(p24.1;q21/2) fusion gene progressed to malignant lymphomas. Abnormalities in the expression and/or activity of STAT3 and JAK2 as well as various JAK2 fusion genes are associated with the development and progression of various myeloproliferative and lymphoproliferative malignancies. These findings suggest that the STAT3-JAK2-fusion gene may contribute to the malignant progression and perhaps development of CD4+ ITCLD-GT.
|
|
The CAP superfamily (cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP)) is a large superfamily of secreted proteins that are produced by a wide range of organisms, including prokaryotes and non-vertebrate eukaryotes. The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences.
|
|