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)

Cell cycle checkpoints appear to contribute to an increase in cell survival and a decrease in abnormal heritable genetic changes following exposure to DNA damaging agents. Though several radiation-sensitive yeast mutants have been identified, little is known about the genes that control these responses in mammalian cells. Recent studies from our laboratory have demonstrated a close correlation between expression of wild-type p53 genes in human hematopoietic cells and their ability to arrest in G1 phase after certain types of DNA damage. In the present study, this correlation was first generalized to nonhematopoietic mammalian cells as well. A cause and effect relationship between expression of wild-type p53 and the G1 arrest that occurs after gamma irradiation was then established by demonstrating (i) acquisition of the G1 arrest after gamma irradiation following transfection of wild-type p53 genes into cells lacking endogenous p53 genes and (ii) loss of the G1 arrest after irradiation following transfection of mutant p53 genes into cells with wild-type endogenous p53 genes. A defined role for p53 (the most commonly mutated gene in human cancers) in a physiologic pathway has, to our knowledge, not been reported previously. Furthermore, these experiments illustrate one way in which a mutant p53 gene product can function in a "dominant negative" manner. Participation of p53 in this pathway suggests a mechanism for the contribution of abnormalities in p53 to tumorigenesis and genetic instability and provides a useful model for studies of the molecular mechanisms of p53 involvement in controlling the cell cycle.
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PMID:Wild-type p53 is a cell cycle checkpoint determinant following irradiation. 132 40

Primary human papillomavirus (HPV) positive anogenital cancers normally develop without somatic mutation within the p53 gene. In this study, however, we have identified p53 point mutations in metastases arising from HPV positive cervical carcinomas, suggesting that acquisition of p53 mutation may play a role in the progression of some HPV associated primary cancers. p53 mutants identified in anogenital cancers exhibit a dominant transforming phenotype and increased resistance to HPV16 E6 directed degradation. The association of p53 mutation with metastases may explain the poor prognosis reported for HPV negative primary cancers, many of which already contain mutant p53. A high proportion of p53 mutations detected in both primary and metastatic cancers are GC-->TA transversions, strongly suggesting a role for external carcinogens in the development of these cancers.
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PMID:Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. 132 51

In this study 125 primary lung tumours have been immunostained with a panel of 5 anti-p53 antibodies (PAb240, PAb421, PAb1801, CM-1 and C19). These antibodies recognise different epitopes over the full extent of the p53 gene. It is generally believed that immunolabelling identifies only mutant p53 proteins due to the short half life of the wild type protein. The aims of this study were to confirm earlier studies of p53 positivity in human lung tumours and to establish whether or not this bore any relationship to survival. Immunostaining was demonstrated within the nuclei of affected cells in 54% of the 125 lung tumours (59% of 78 squamous cell carcinomas, 52% of 42 adenocarcinomas and 20% of five small cell carcinomas). This confirms previous smaller studies of p53 protein expression in human lung tumours. Survival curves have been drawn for all of the cases considered together and for squamous and adenocarcinomas separately. No differences in survival between p53 positive and negative cases were seen for any group of tumours. This indicates that although p53 may be of considerable importance in the initiation of malignancy it is probably of little significance once a tumour has developed.
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PMID:The relationship of p53 immunostaining to survival in carcinoma of the lung. 132 7

Mutant p53 has been found in a wide variety of human malignancies including carcinomas of the lung, breast and colon. Because of the controversial mutational rate of the p53 gene in hepatocellular carcinoma, a large series of liver tumors from white patients with different risk factors was examined immunohistochemically for expression of the p53 mutant to assess its prevalence and the relationships between p53 overexpression and clinicopathological data. Nine of 58 specimens were found to have detectable evidence of p53 gene mutation by virtue of the immunohistochemical detection of mutant p53 protein. The p53 mutation was more frequent in patients with serological hepatitis B and C markers than in patients without these markers (p = 0.046). The prevalence of p53-positive tumors was also significantly higher in the group of tumors with invaded portal branches than in the group without (p = 0.02). Our results showed that p53-positive hepatocellular carcinoma is a rare finding in patients exposed to a low dietary aflatoxin intake and that p53 mutation seems to occur at a late stage of the tumoral process and could contribute to an aggressive tumoral phenotype.
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PMID:Overexpression of p53: a rare event in a large series of white patients with hepatocellular carcinoma. 133 Aug 67

The p53 product is frequently mutated in human tumors. Both acquired and inherited mutations have been described. These mutations transform p53 from a growth suppressor gene to a transforming oncogene. We examined tissue from 6 patients with primary lung carcinoma and the corresponding brain metastases for the presence of p53 mutations by immunohistochemistry. We then confirmed and characterized the mutations by single strand conformation analysis and by direct sequence analysis. All 6 patients had primary and metastatic tumor expressing a mutant p53. The mutations were all G-T transversions and mapped to exons 5, 6, 7, and 8. The mutations in the primary tumors were precisely conserved in the brain metastases.
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PMID:p53 gene mutations in primary lung tumors are conserved in brain metastases. 133 52

The products of the two major suppressor genes p53 and Rb interact with the oncogene products of the DNA tumour viruses. These viral-host protein interactions mimic and interfere with the normal interactions of p53 and Rb with host proteins. The Rb gene product is frequently mutated in human cancers such that it no longer binds to viral or host proteins. In contrast we find that this is not the case with p53 as some, but not all, mutant p53 proteins still bind to the SV40 T antigen. In particular the hot spot mutation found in most Chinese and African cases of hepatocellular carcinoma (HCC) retains T binding activity. The simple subdivision of different p53 mutations revealed by this analysis may have diagnostic and prognostic consequences.
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PMID:Diversity of human p53 mutants revealed by complex formation to SV40 T antigen. 133 35

Drug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which confers cross-resistance to hydrophobic natural product cytotoxic drugs. Expression of the MDR1 gene can occur de novo in human cancers in the absence of drug treatment. The promoter of the human MDR1 gene was shown to be a target for the c-Ha-Ras-1 oncogene and the p53 tumor suppressor gene products, both of which are associated with tumor progression. The stimulatory effect of c-Ha-Ras-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. These results imply that the MDR1 gene could be activated during tumor progression associated with mutations in Ras and p53.
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PMID:Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. 134 76

Nasopharyngeal carcinoma (NPC) is a malignancy which is consistently associated with the Epstein-Barr virus (EBV). The structure of the EBV genome in NPC suggests that NPC is a clonal proliferation of epithelial cells which emerges after EBV infection. The disease develops with high incidence in specific populations in discrete geographic locations, implicating possible genetic or environmental cofactors. Mutations of the p53 gene are among the most frequent genetic changes found in a large variety of human tumors. Mutations in p53 have been shown to abrogate the suppressor function of wild-type p53 and thus contribute to the transformed phenotype. To determine if mutation in p53 participates in the development of the malignant clone in NPC, the structure and sequence of p53 in 42 primary, metastatic, and nude mouse-passaged NPC specimens was analyzed. A high frequency (6 of 9) of mutations was detected in the nude mouse-passaged tumors, while only 2 of 15 metastatic and 0 of the 18 primary tumors harbored mutant p53. The p53 mutations included single-point mutations and more extensive changes such as frame shifts, deletion, duplication, or complete loss of coding sequences. These data indicate that alterations of the p53 gene are unlikely to be involved in the initial genetic events leading to the clonal outgrowth in NPC. However, although it is a rare NPC which can be established in nude mice, this growth advantage appears to be conferred on tumors bearing a mutant p53.
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PMID:Alterations of the p53 gene in nasopharyngeal carcinoma. 134 27

Inactivation of the protein product of the wild-type tumour suppressor gene p53 through complexing of the protein with the E6 oncoprotein of human papillomaviruses (HPV) in HPV-infected cells is thought to be important in the aetiology of cervical carcinoma. Mutations of p53 have also been reported in HPV-negative carcinomas, and we now demonstrate loss of heterozygosity (LOH) of chromosome region 17p13 (in which p53 is located) in such tumours. Immunocytochemical staining with monoclonal antimutant-p53 antibody revealed that the carcinomas with LOH on 17p and completely lacking HPV DNA sequences had mutant p53. Thus the LOH had apparently resulted in the loss of the wild-type allele. Consequently, in both HPV-positive and HPV-negative tumours there is loss of function of wild-type p53, in the former because the protein product of the p53 gene complexes with that of the viral E6 gene, in the latter because the protein is altered, presumably as a result of a direct alteration of the p53 gene but possibly because of other post-translational changes. That this mutant allele of the tumour suppressor gene may sometimes behave like an oncogene is suggested by the presence of more than the expected number of copies of the remaining chromosome 17 homologue in some carcinomas.
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PMID:Loss of heterozygosity on chromosome 17p and mutant p53 in HPV-negative cervical carcinomas. 135 66

Mutation of the p53 tumor suppressor gene is a recurring event in a variety of human cancers. Wild-type p53 may regulate cell proliferation and has recently been shown to repress transcription from several cellular promoters. We studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen promoter and on several viral promoters including the simian virus 40 early promoter-enhancer, the herpes simplex virus type 1 thymidine kinase and UL9 promoters, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus, human immunodeficiency virus type 1, and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and plasmids containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. Expression of wild-type p53 correlated with a consistent and significant (6- to 76-fold) reduction of reporter enzyme activity. A mutation at amino acid 143 of p53 releases this inhibition significantly with all the promoters studied. Expression of a p53 mutated at any one of the five amino acid positions 143, 175, 248, 273, and 281 also correlated with a much smaller (one- to sixfold) reduction of reporter enzyme activity from the herpes simplex virus type 1 thymidine kinase promoter. These mutant forms of p53 are found in various cancer cells. Thus, failure of tumor suppression correlates with loss of the promoter inhibitory effect of p53.
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PMID:Inhibition of viral and cellular promoters by human wild-type p53. 135 31


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