Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A tumour suppressor function for p53 is indicated in human lung cancer and in carcinoma of the colorectum. Loss of suppressor function, by mutation of the p53 gene, is associated with activation of p53 as an oncogene. The suppressor (wild type) and oncogenic (mutant) forms of the murine p53 protein are distinguishable at the molecular level by reactivity with anti-p53 monoclonal antibodies. For example, activated mutant p53 fails to react with PAb246 (p53-246 degrees). We now demonstrate that wild type p53 mRNA can be expressed either as p53-246+ or p53-246 degrees. We propose that p53-246 degrees may represent an allosteric variant of wild type p53 compatible with positive growth control. Thus, for wild type p53 the variants p53-246+ and p53-246 degrees may reflect suppressor and activator functions of p53 in the normal control of cell proliferation. For human p53 we present evidence that the epitope recognised by PAb1620 is analogous to that for PAb246 on murine p53. Thus the epitope for PAb1620 may prove to be of use as a marker for wild type human p53 with anti-oncogenic function.
Br J Cancer 1990 Apr
PMID:Evidence for allosteric variants of wild-type p53, a tumour suppressor protein. 213 77

The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss-of-function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first mutation at the p53 locus resulting in a trans-dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild-type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged. The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53.
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PMID:Tumor suppressor genes. 214 May 9

The p53 gene has been a constant source of fascination since its discovery nearly a decade ago. Originally considered to be an oncogene, several convergent lines of research have indicated that the wild-type gene product actually functions as a tumour suppressor gene. For example, expression of the neoplastic phenotype is inhibited, rather than promoted, when rat cells are transfected with the murine wild-type p53 gene together with mutant p53 genes and/or other oncogenes. Moreover, in human tumours, the short arm of chromosome 17 is often deleted. In colorectal cancers, the smallest common region of deletion is centred at 17p13.1; this region harbours the p53 gene, and in two tumours examined in detail, the remaining (non-deleted) p53 alleles were found to contain mutations. This result was provocative because allelic deletion coupled with mutation of the remaining allele is a theoretical hallmark of tumour-suppressor genes. In the present report, we have attempted to determine the generality of this observation; that is, whether tumours with allelic deletions of chromosome 17p contain mutant p53 genes in the allele that is retained. Our results suggest that (1) most tumours with such allelic deletions contain p53 point mutations resulting in amino-acid substitutions, (2) such mutations are not confined to tumours with allelic deletion, but also occur in at least some tumours that have retained both parental 17p alleles, and (3) p53 gene mutations are clustered in four 'hot-spots' which exactly coincide with the four most highly conserved regions of the gene. These results suggest that p53 mutations play a role in the development of many common human malignancies.
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PMID:Mutations in the p53 gene occur in diverse human tumour types. 253 45

The cdk inhibitor p21WAF1/Cip1 (p21), which can be transcriptionally activated by p53, functions to block cell cycle progression. In this study, we analysed the expression of p21 in normal and reactive brain and in gliomas of various malignancy grades. Southern blotting showed no p21 gene deletion. Western blotting and immunohistochemical assay showed that the levels of p21 protein in normal and reactive brain tissue were very low; however, p21 was elevated in a majority of gliomas tested, regardless of their malignancy grades. In glioblastoma multiforme, marked elevation of p21 was observed in samples harboring either wild-type or mutant p53. But, in anaplastic astrocytomas, the level of p21 was not elevated in samples harboring mutant-type p53. Immunohistochemical staining of paraffin-embedded astrocytomas and glioblastomas showed that tumor cells and not contaminating normal cells were positive for p21. Therefore, overexpression of p21 appears to be an early event in the development of glial neoplasms and p53-dependent p21 expression appears to be tumor grade specific.
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PMID:Increased levels of p21WAF1/Cip1 in human brain tumors. 747 21

Modulation of apoptosis may influence resistance to chemotherapy and therefore affect the outcome of cancer treatment. Ovarian cancer, one of the most fatal malignancies in women, is often associated with drug resistance but the cellular pathways contributing to this effect remain obscure. We have found that Bcl-2 and p53, two proteins implicated in the control of apoptosis, are frequently expressed in fresh biopsies of primary ovarian carcinoma. Examination of Bcl-2 and p53 protein levels in pairs of cis-platin sensitive and resistant ovarian cell lines demonstrated that the resistant variants over-express Bcl-2 and/or p53, apparently due to progressive expansion of Bcl-2 and/or p53 positive subpopulations during the in vitro development of resistance. Exogenous expression of Bcl-2 or a temperature sensitive mutant p53 (ts p53) in the ovarian cell line A2780 resulted in protection from drug-induced apoptosis and a delay in drug-mediated S-phase arrest. Interestingly, p53 accumulation in response to DNA damage induced by different agents was significantly delayed and reduced in the Bcl-2 transfectants compared to the control A2780 line, suggesting that Bcl-2 may act upstream of the p53 pathway. Similarly, the induction of Bax mRNA and protein was also found to be delayed in the presence of Bcl-2. Overall, our data provide further evidence for cross-talk between Bcl-2, p53 and Bax and suggest that these genes are important determinants of drug-induced apoptosis thereby modulating resistance to chemotherapy.
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PMID:The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. 747 41

A common feature of human tumor tissue is mutant p53 protein accumulation. Here we evaluate a new "sandwich" immunoassay for p53 protein incorporating modifications to a previously reported method, including the use of microtiter plates coated directly with the anti-p53 monoclonal antibody DO-1, a detergent- and mouse serum-containing sample diluent, and a labeled secondary antibody diluent containing goat serum. The use of CM-1 antiserum to probe the immunocaptured p53 and the detection of bound complexes by a labeled secondary antibody allows coupling to a time-resolved fluorescence detection system. The new assay yielded p53 concentrations comparable with those by the previous assay for breast tumor cytosols (n = 198), nondiseased breast tissues (n = 70), and five transformed cell lines, but showed differences in p53 values measured in sera from patients without cancer (n = 78). These serum differences were found to reflect nonspecific interferences affecting the original method, which implies that the new immunoassay has improved specificity for serum p53 quantification.
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PMID:Time-resolved immunofluorometric assay of p53 protein. 749 12

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.
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PMID:Serum oncoproteins in asbestosis patients. 749 43

The p53 tumor suppressor gene is believed to be the most commonly mutated gene in human cancer. p53 is thought to function as a negative regulator of the cell cycle, arresting cells in the G1 phase. This study examined the effects of different mutagenic environments on the incidence of p53 overexpression in squamous cell carcinomas (SCCs) from sun exposed and non-sun exposed squamous epithelium. An immunohistochemical analysis was undertaken in an attempt to assay SSC for p53 overexpression, an indirect measure of missense mutant p53. Positive nuclear staining for p53 was observed in 14 of 21 sun exposed SCCs, two of 19 vulvar/perianal SCCs, and 15 of 20 oral cavity SCCs. The number of positive anogenital tumors was low compared with that of both sun exposed (chi-squared, 1 df, P = .0004) and oral (chi-squared, 1 df, P < .0001) sites. It was concluded that p53 protein accumulation is common in sun-exposed cutaneous SCC and oral SCC compared with anogenital SCC, and thus it is hypothesized that the nature of the mutagenic environment in which SCC develops directly affects the incidence of immunohistochemically detectable p53-positive cells.
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PMID:Site-specific comparison of p53 immunostaining in squamous cell carcinomas. 753 84

This study examined the effect of transforming growth factor beta-1 (TGF-beta 1) on c-myc, RB1, junB and p53 expression together with pRb phosphorylation, in carcinoma-derived and normal human oral keratinocytes with a range of inhibitory responses to this ligand. Amplification of c-myc was observed in eight of eight tumour-derived cell lines and resulted in corresponding mRNA expression. The down-regulation of c-myc expression by TGF-beta 1 predominantly reflected growth inhibition by TGF-beta 1, but in two of eight tumour-derived cell lines which were partially responsive to TGF-beta 1 c-myc expression was unaltered by this ligand. While RB1 mRNA levels were unaltered by TGF-beta 1, the ligand caused the accumulation of the underphosphorylated form of the Rb protein in all cells irrespective of TGF-beta 1-induced growth arrest. junB expression was up-regulated by TGF-beta 1 in cells with a range of growth inhibitory responses. All cells contained mutant p53. TGF-beta 1 did not affect p53 mRNA expression in both tumour-derived and normal keratinocytes and there was no alteration in p53 protein levels in keratinocytes expressing stable p53 protein following TGF-beta 1 treatment. The data indicate that TGF-beta-induced growth control can exist independently of the presence of mutant p53 and the control of Rb phosphorylation and c-myc down-regulation. It may be that TGF-beta growth inhibition occurs via multiple mechanisms and that the loss of one pathway during tumour progression does not necessarily result in the abrogation of TGF-beta-induced growth control.
Br J Cancer 1995 Oct
PMID:Effects of transforming growth factor beta-1 on growth-regulatory genes in tumour-derived human oral keratinocytes. 754 41

Many recent studies have implicated p53 in the cellular response to injury and induction of cell death by apoptosis. In a rat embryonal fibroblast cell line transformed with c-Ha-ras and a mutant temperature-sensitive p53 (val135), cells were G1 arrested at the permissive temperature of 32 degrees C when overexpressed p53 was in wild-type conformation. In this state cells were resistant to apoptosis induced by etoposide (at up to 50 microM) or bleomycin (15 microU ml-1). Cells at 37 degrees C with overexpressed p53 in mutant conformation were freed from this growth arrest, continued proliferating and showed dose-dependent increases in apoptosis. This death is independent of wild-type p53 function. Control cells containing a non-temperature-sensitive mutant p53 (phe132) were sensitive to both etoposide and bleomycin after 24 h at 32 degrees C and 37 degrees C, indicating that the results are not simply due to temperature effects on pharmacokinetics or DNA damage. Our data show that induction of a stable p53-mediated growth arrest renders these cells much less likely to undergo apoptosis in response to certain anti-cancer drugs, and we conclude that the regulatory role of p53 in apoptosis is influenced by the particular cellular context in which this gene is expressed.
Br J Cancer 1995 Oct
PMID:p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs. 754 47


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