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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes whose expression patterns are altered in a cell line immortalized by mutant p53 were isolated by differential screening of a cDNA library. Levels of alpha 1 (I) collagen mRNA were reduced in the majority of immortalized cell lines which greatly overproduced the transfected mutant p53. This may reflect a co-selection during the establishment of the cell lines, rather than a direct effect of p53 on alpha 1 (I) collagen gene expression. On the other hand, a more direct relationship could be demonstrated between the expression of activated ras and a reduction in alpha 1 (I) collagen mRNA. Such reduction could partially account for the effects of ras on cell shape and cell proliferation.
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PMID:Reduced levels of alpha 1 (I) collagen mRNA in cells immortalized by mutant p53 or transformed by ras. 175 78

The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.
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PMID:Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. 176 70

Mutations in the p53 tumor-suppressor gene have been implicated in the pathogenesis of a significant proportion of human cancers and in a dominantly inherited familial cancer syndrome (Li-Fraumeni syndrome). Frequent rearrangements and point mutations have also been detected in the p53 gene in the murine erythroleukemias induced by Friend leukemia virus. We have previously reported that transgenic mice overproducing a mutated p53 protein are predisposed to the development of lung carcinomas, bone and soft-tissue sarcomas, as well as lymphoid malignancies. Here we report that p53 transgenic mice infected with the polycythemia-inducing strain of Friend virus (FV-P) progress to the late stage of erythroleukemia more rapidly than do normal mice. In addition, Friend leukemic cell lines derived from p53 transgenic mice overproduce mutant p53 protein and show a high frequency of rearrangement of the ets-related Spi-1 oncogene, as previously reported in Friend cell lines derived from non-transgenic animals. These results suggest that the same genetic changes involved in the evolution of Friend leukemia in normal mice are also required in mice with an inherited predisposition to cancer. The data also indicate that p53 transgenic mice provide an animal model in which to analyse the role that genetic and environmental factors play in influencing cancer predisposition.
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PMID:p53 transgenic mice: accelerated erythroleukemia induction by Friend virus. 176 68

Transforming growth factor beta 1 (TGF beta 1) is the prototype of a large family of polypeptides involved in growth control, extracellular matrix production, and development. The TGF beta s have marked stimulatory effects on connective tissue formation. They are chemotactic for fibroblasts, indirect mitogens for certain mesenchymal cells and stimulators of extracellular matrix deposition. The TGF beta s are also potent inhibitors of proliferation of most cell types in culture, and in vivo studies have indicated that the predominant effect of TGF beta 1 on cell proliferation is inhibition. We have investigated the mechanism of TGF beta 1 inhibition of skin keratinocyte growth. Earlier studies demonstrated that TGF beta 1 inhibition of keratinocyte proliferation involves suppression of c-myc transcription, and indirect evidence suggested that the product of the retinoblastoma tumor susceptibility gene, pRB, may be involved in this process. More recently, we have shown that transient expression of pRB in skin keratinocytes can repress human c-myc promoter/CAT transcription as effectively as TGF beta 1. The same c-myc promoter region, termed the TGF beta control element (TCE), was required for regulation by both TGF beta 1 and pRB. Oligonucleotides containing the TCE bound to several nuclear factors in mobility shift assays and a cellular protein of approximately 106 kD in Southwestern assays. Binding of these factors could be demonstrated in cells with or without normal pRB, and the binding of some factors was rapidly inhibited by TGF beta 1 treatment of TGF beta-sensitive but not TGF beta-insensitive cells. These data indicate that pRB can function to inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF beta 1 pathway for suppression of c-myc transcription. Studies with other cell types have shown that another tumor suppressor gene, p53, can also regulate transcription of c-myc in transient assays. Whereas wild type p53 markedly suppressed transcription, four different mutant p53 clones caused transactivation. The data support the hypothesis that pRB and p53 can both cause growth inhibition by blocking the expression of the protooncogene, c-myc, and indicate that tumor suppressor genes may function in the response pathway for diffusible negative growth regulators such as TGF beta.
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PMID:TGF beta regulation of epithelial cell proliferation: role of tumor suppressor genes. 184 40

The E7 protein is one of the principle transforming proteins encoded by human papillomavirus type 16 (HPV16), a virus strongly associated with the development of cervical carcinoma. In the present study we show that cotransfection of wild-type human or murine p53 sequences with E7 and ras markedly reduces transformation in baby rat kidney cells, although no effect of p53 is seen on the ability of E7 to transform an established mouse line to anchorage independence. In contrast, expression of mutant p53 strongly potentiates the transforming function of E7 and confers marked growth factor independence to cells cotransformed by E7 and ras. These data suggest that E7 and p53 function in separate yet complementary biochemical pathways.
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PMID:Modulation of immortalizing properties of human papillomavirus type 16 E7 by p53 expression. 184 4

The p53 gene encodes a phosphoprotein which binds DNA. Many types of tumors contain mutant p53 genes, but the effects of these mutations on the intrinsic properties of p53 are largely unknown. In the present study, we tested the effect of p53 mutations on DNA-binding. Each of 15 different mutant p53 gene products derived from human tumors or mouse transformants bound calf thymus DNA more weakly than did wild-type products. A significant subset of mutant proteins were also found to be underphosphorylated compared to the wild-type protein when produced in a reticulocyte lysate system, but this did not appear to explain the pattern of alterations of DNA-binding. The tested mutations were dispersed over several regions of the p53 gene and included representatives of all four of the evolutionarily conserved domains that are the known 'hot spots' for p53 mutation. The results suggest common pathways by which these various mutations affect the normal function of p53.
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PMID:Mutant p53 proteins bind DNA abnormally in vitro. 184 54

Human hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G----T transversion in seven HCC DNA samples and the G----C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5,6,8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains, which include codon 249 (refs 4-9). We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.
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PMID:Mutational hotspot in the p53 gene in human hepatocellular carcinomas. 201 Nov 86

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.
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PMID:Relation between p53 overexpression and established prognostic factors in breast cancer. 185 36

It has been reported [Matlashewski et al. (1986). Eur. J. Biochem., 154, 665-672] that HeLa cells contain no detectable p53 protein, although they contain p53 mRNA which is translationally active. Here it is shown that endogenous HeLa p53 proteins were easily detected in HeLa cells transiently expressing mouse deletion mutant p53 gene after transfection with the appropriate recombinant plasmid. This detection was obtained by immunoprecipitation coupled with SDS-PAGE as well as by Western blotting experiments. Our results strongly suggest that HeLa p53 mRNA is actually translated in vivo, generating an extremely unstable p53 protein. Considering that the HeLa cell line is a HPV-18-positive human cervical carcinoma cell line, this high instability of HeLa p53 proteins is in keeping with the finding that E6 oncoprotein encoded by human papillomavirus 16 or 18 promotes the degradation of p53 proteins [Scheffner et al. (1990). Cell, 63, 1129-1136].
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PMID:Endogenous HeLa p53 proteins are easily detected in HeLa cells transfected with mouse deletion mutant p53 gene. 188 12

Mutations in the p53 gene are associated with a wide variety of human tumors, including those of the breast. To assess functionally the role of the p53 gene in the development of human breast cancer, we introduced either wild-type or mutant p53 cDNA into three human breast cancer cell lines by DNA transfection. The cell lines MDA-MB 468 and T47 D contain only single mutated copies of the p53 gene, whereas the status of p53 in the breast cancer cell line MCF 7 remains equivocal. Following transfection, MCF 7 cells continued to grow unaffected both in vitro and in vivo in the presence of high levels of expression of the exogenous wild-type p53 gene. In contrast, however, the continued expression of an exogenous wild-type p53 gene was incompatible with cellular growth in both the MDA-MB 468 and T47 D cell lines. Elevated levels of expression of the exogenous mutant p53 gene did not alter the growth of the cell lines in vitro. These data strongly suggest that the wild-type p53 gene can function as a suppressor of cellular growth in breast cancer cells. That the wild-type p53 gene does not suppress the growth of MCF 7 cells indicates that at least some human breast tumors can arise without functional inactivation of the p53 gene by mutation. These tumors may represent a separate prognostic group.
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PMID:Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. 192 4


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