Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A point mutation at codon 129 of the murine erythropoietin receptor (cEpoR) results in constitutive activation. We have generated a recombinant spleen focus-forming retrovirus in which the env gene is replaced by the cEpoR cDNA. Mice infected with this virus (but not by viruses expressing the wild-type EpoR) develop erythrocytosis and splenomegaly. From the spleen of infected animals we have isolated clonal, growth factor-independent, proerythroblast cell lines that express cEpoR, do not express the putative oncogene spi-1, and have rearranged and inactivated expression of the p53 suppressor oncogene. These cells induce erythroleukemia upon injection into mice. This demonstrates that oncogenic point mutations exist in a member of the cytokine receptor superfamily. The activated erythropoietin receptor does not transform cultured fibroblasts, suggesting why oncogenic mutations in other members of this receptor superfamily have not been detected.
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PMID:An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. 166 16

In this report, we describe the isolation and characterization of six murine squamous cell carcinoma cell lines (BPCC) derived from carcinomas produced by a complete carcinogenesis protocol with benzo[a]pyrene (B[a]P). All six cell lines were tumorigenic to varying degrees in nude mice, and several were spontaneously metastatic to the lungs. The in vivo invasive potential of each BPCC cell line was determined using de-epithelialized tracheal xenotransplants into which cells were inoculated. This assay revealed positive association of tumor grade with in vivo invasiveness, yet no clear relationship to the spontaneous metastatic potential of the cell lines, suggestive that invasive potential is only one determinant of the overall metastatic phenotype. At the molecular level, all six BPCC cell lines revealed the absence of mutations in the H-ras oncogene and no amplification or rearrangement in the cycl 1/cyclin D1 putative oncogene. Analysis of the p53 tumor suppressor gene revealed a direct correlation between positive nuclear immunohistochemical staining of the p53 protein in four BPCC cell lines and the presence of p53 mutations identified by direct sequence analysis. The localization of mutations to exons 7 and 8 of the p53 gene and the detection of G to T transversions in two of the four cell lines bearing p53 mutations are in agreement with previous analyses of a large series of primary B[a]P-induced murine skin tumors. In addition, frameshift mutations were identified in two cell lines. The correlation of the biological and molecular properties of these BPCC cell lines with the known characteristics of primary squamous cell carcinomas induced by B[a]P indicates that these cell lines could be useful tools in elucidating the mechanisms of tumorigenesis of this important chemical carcinogen.
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PMID:Murine squamous cell carcinoma cell lines produced by a complete carcinogenesis protocol with benzo[a]pyrene exhibit characteristic p53 mutations and the absence of H-ras and cyl 1/cyclin D1 abnormalities. 805 40

Cloning of the t(14;18) translocation breakpoint resulted in the identification of a new putative oncogene, which mapped to 18q21, termed bcl-2. The t(14;18) resulted in inappropriately high levels of bcl-2 expression in follicular lymphoma. Prospective studies using mice transgenic for a human bcl-2-immunoglobulin minigene, intended to recreate the molecular features of the t(14;18), demonstrated that bcl-2 gene deregulation was oncogenic. Interestingly, overexpression of bcl-2 showed no demonstrable influence on rates of cellular proliferation. Rather, bcl-2 was found to extend cellular viability by blocking apoptosis. Recent studies with other oncogenes and tumor suppressor genes, such as c-myc and p53, have demonstrated that the deregulation of apoptosis may be of general significance in the development of multiple types of cancer and appears to be a critical event during multistep carcinogenesis. The selective induction of apoptosis in tumor cell populations is now being considered in the design of novel therapeutic interventions.
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PMID:The bcl-2 oncogene: apoptosis and neoplasia. 827 71

Amongst the human astrocytic tumours, the commonest of primary brain tumours, the clinical outcome of astrocytoma (AS) is significantly better than anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Often, low grade tumours can progress to or recur with a more malignant phenotype. Recent loss of heterozygosity (LOH) reports suspect the involvement of a tumour suppressor gene, different from p53, in the 17p13.3 region of the human chromosome. However, the effect of LOH of 17p13.3 region on tumour histology at presentation and prognosis is as yet undefined. As a first step to define the role of this putative oncogene in astrocytic tumour progression, we correlated the LOH of a locus, D17S379, in 17p13.3 region and the p53 locus in 17p13.1 region with the histopathology of astrocytic tumours by PCR based microsatellite and restriction fragment length polymorphism of DNA extracted from microdissected paraffin sections of 45 astrocytic tumours of different histopathological grades. LOH of D17S379 was significantly associated (P=0.02) with AA and GBM (high grade malignancy), while no such preferential association was found with LOH of p53. There were no mutations in the exons 5 to 9 of p53 gene in the five tumours with LOH of D17S379 but not of p53 region. In a case of AA with a heterogenous microscopic appearance, heterozygosity of D17S379 was lost only in the area with a more malignant histology while both areas had no LOH or mutation of p53. A locus at the 17p13.3 region, independent of the p53 locus, is involved in a large subset of astrocytic tumours during transformation into a more malignant phenotype, and thus may be a link in the chain of genetic events occurring in astrocytic tumour progression.
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PMID:Loss of heterozygosity of a locus on 17p13.3, independent of p53, is associated with higher grades of astrocytic tumours. 926 74

Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.
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PMID:Genetics and ovarian carcinoma. 963 40

Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.
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PMID:Aberrant regulation of survivin by the RB/E2F family of proteins. 1527 87

Jaceosidin (4',5,7-trihydroxy-3',6-dimethoxyflavone) was isolated from Artemisia argyi as a putative oncogene inhibitor. Jaceosidin inhibited binding between oncoprotein E6 of the human papillomavirus and the p53 tumor suppressor protein. In addition, jaceosidin inhibited binding between the E7 oncoprotein and the Rb tumor suppressor protein, and also inhibited the function of HPV-16 harboring cervical cancer cells, including SiHa and CaSki. Collectively, jaceosidin inhibited the functions of the E6 and E7 oncoproteins of the human papillomavirus, suggesting that this compound might be used as a potential drug for the treatment of cervical cancers associated with the human papillomavirus.
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PMID:Inhibitory effect of jaceosidin isolated from Artemisiaargyi on the function of E6 and E7 oncoproteins of HPV 16. 1581 70

Specific sites of lysine methylation on histones correlate with either activation or repression of transcription. The tumour suppressor p53 (refs 4-7) is one of only a few non-histone proteins known to be regulated by lysine methylation. Here we report a lysine methyltransferase, Smyd2, that methylates a previously unidentified site, Lys 370, in p53. This methylation site, in contrast to the known site Lys 372, is repressing to p53-mediated transcriptional regulation. Smyd2 helps to maintain low concentrations of promoter-associated p53. We show that reducing Smyd2 concentrations by short interfering RNA enhances p53-mediated apoptosis. We find that Set9-mediated methylation of Lys 372 inhibits Smyd2-mediated methylation of Lys 370, providing regulatory cross-talk between post-translational modifications. In addition, we show that the inhibitory effect of Lys 372 methylation on Lys 370 methylation is caused, in part, by blocking the interaction between p53 and Smyd2. Thus, similar to histones, p53 is subject to both activating and repressing lysine methylation. Our results also predict that Smyd2 may function as a putative oncogene by methylating p53 and repressing its tumour suppressive function.
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PMID:Repression of p53 activity by Smyd2-mediated methylation. 1710 71

Overexpression of the DEK gene is associated with multiple human cancers, but its specific roles as a putative oncogene are not well defined. DEK transcription was previously shown to be induced by the high-risk human papillomavirus (HPV) E7 oncogene via E2F and Rb pathways. Transient DEK overexpression was able to inhibit both senescence and apoptosis in cultured cells. In at least the latter case, this mechanism involved the destabilization of p53 and the decreased expression of p53 target genes. We show here that DEK overexpression disrupts the normal differentiation program in a manner that is independent of either p53 or cell death. DEK expression was distinctly repressed upon the differentiation of cultured primary human keratinocytes, and stable DEK overexpression caused epidermal thickening in an organotypic raft model system. The observed hyperplasia involved a delay in keratinocyte differentiation toward a more undifferentiated state, and expansion of the basal cell compartment was due to increased proliferation, but not apoptosis. These phenotypes were accompanied by elevated p63 expression in the absence of p53 destabilization. In further support of bona fide oncogenic DEK activities, we report here up-regulated DEK protein levels in both human papilloma virus-positive hyperplastic murine skin and a subset of human squamous cell carcinomas. We suggest that DEK up-regulation may contribute to carcinoma development at least in part through increased proliferation and retardation of differentiation.
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PMID:DEK proto-oncogene expression interferes with the normal epithelial differentiation program. 1903 8

Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3beta phosphorylation at Ser9, stabilization and nuclear localization of beta-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27(Kip1) phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.
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PMID:Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. 1907 42


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