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

We show that wild-type human p53 transactivates the human epidermal growth factor receptor (EGFR) promoter in vivo in a dose-dependent manner, implicating p53 in promotion of cell proliferation. This activation is sensitive to the expression of cellular oncoprotein MDM2 and human papillomavirus type 18 (HPV-18) E6 protein. The p53 response element is localized within -15 and -569 of the promoter. The EGFR promoter does not have a TATA box, and has low activity in Saos-2 cells in the absence of p53. Results from our in vivo transient transfection assays suggest that p53-binding sites, without any other known promoter element, can act as bidirectional promoters in the presence of wild-type p53. Gel retardation analyses suggest that p53 may serve to nucleate TBP on a promoter. We propose that p53 successfully nucleates the transcription complex, possibly via direct interaction with TFIID, and activates the EGFR promoter.
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PMID:Wild-type human p53 activates the human epidermal growth factor receptor promoter. 815 94

Human papillomavirus (HPV) is frequently associated with cervical carcinoma. Inactivation of the p53 tumor suppressor gene product by binding to the HPV encoded E6 protein is considered as an important pathway for malignant progress in HPV-infected cells. In contrast, mutations of the p53 gene have been found in HPV-negative cervical carcinoma cells. To evaluate the involvement of p53 inactivation for the development of genital carcinoma, we determined the state of the p53 gene in 20 genital precancer lesions and carcinomas, which had been previously studied for the expression of p53 protein and the presence of HPV DNA. Exons 5 through 9 of the p53 gene were analyzed by single-strand conformation polymorphism analysis of polymerase chain reaction (PCR)-amplified DNA fragments, and the results obtained by the PCR-SSCP analysis were confirmed by DNA sequencing. No mutations were detected in any of the specimens, including the three HPV-negative cases. The present results suggest that the functional inactivation of p53 is not invariably required for the induction of malignant transformation in the genital tract, and thus other genetic events can also significantly participate in genital carcinogenesis.
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PMID:The state of the p53 gene in human papillomavirus (HPV)-positive and HPV-negative genital precancer lesions and carcinomas as determined by single-strand conformation polymorphism analysis and sequencing. 816 46

Transient transfection experiments indicated (i) that E6 protein of non-cancer-associated cutaneous human papillomavirus type 1 (HPV-1) can inhibit p53-mediated transcriptional transactivation in both p53-deficient human cells (H358) and normal rat cells (3Y1), but those of cancer-associated cutaneous HPV-5, -8, and -47 cannot do so in either H358 or 3Y1 cells, and (ii) that E6 proteins of HPV-16 and -18 can inhibit the p53 function in H358 cells but not in 3Y1 cells.
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PMID:Inhibition of p53-mediated transactivation by E6 of type 1, but not type 5, 8, or 47, human papillomavirus of cutaneous origin. 820 40

The two major transforming proteins of oncogenic human papillomaviruses are encoded by the E6 and E7 oncogenes. Both viral proteins interact specifically with the products of cellular human tumour suppressor genes; E6 with p53 and E7 with Rb. However, the mechanism of action of E6 is still poorly understood in comparison with that of E7. Although extensive in vitro studies have been done with mutant E6 proteins, very little is known about the activities of E6 in vivo. In this study we have analysed the structure-function relationships of HPV-18 E6 in in vitro analyses and we correlate this with in vivo activity. These studies define a number of domains on the E6 molecule which are involved in the ability of E6 to target p53 for degradation in vitro. This analysis demonstrates that domains previously shown to be important in HPV-16 E6 (Crook et al., 1991; Mietz et al., 1992) are also conserved in HPV-18 and also reconciles the differences between these reports. A series of in vivo studies demonstrate that E6 mediated degradation of p53 in vitro is irrelevant both for cell transformation and for the ability of E6 to abolish p53 transcriptional activation. In addition, we show that at least four distinct regions of the E6 protein are involved in the p53 association in vivo.
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PMID:Mutational analysis of HPV-18 E6 identifies domains required for p53 degradation in vitro, abolition of p53 transactivation in vivo and immortalisation of primary BMK cells. 820 32

The role tumor suppressors p53 and retinoblastoma (RB) play in the transformation process has become central to understanding the pathogenesis of DNA tumor viruses. The two oncoproteins of human papillomavirus (HPV)-16, E6 and E7, bind to p53 and RB, respectively, thus inactivating the function of these tumor suppressor genes. Immortalization of primary human foreskin epithelial cells by HPV requires expression of the E7 protein, and the E6 protein greatly enhances the immortalization frequency. Two of three cell lines immortalized by the HPV-16 E7 oncoprotein expressed wild-type p53 and only one of the three cell lines had acquired a p53 mutation and loss of heterozygosity at 17p during the immortalization process. All three E7-immortalized lines contained higher steady-state levels of p53 protein. Mutation of the p53 gene is not required for immortalization in the absence of the HPV-16 E6 inactivation of the p53 protein, and 16E7 expression leads to the stabilization of wild-type p53.
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PMID:Elevated wild-type p53 protein levels in human epithelial cell lines immortalized by the human papillomavirus type 16 E7 gene. 825 51

Recent evidence suggests that the tumor-suppressor protein p53 functions as a transcriptional regulator to control cell proliferation. An interaction with p53 is required for SV40 T antigen to transform primary cells; however, the effect of T antigen binding on p53 function is not known. In order to determine if an interaction with T antigen results in loss of p53-mediated transcriptional activity, we have used vectors expressing either a p53-GAL4 fusion protein or a wild-type p53 protein in transient co-transfection assays with T-antigen expression vectors. We have demonstrated that coexpression of T antigen significantly reduces both p53-GAL4-mediated transcription from a GAL4-dependent CAT reporter and p53-mediated transcription from a consensus p53 binding site in vivo. Moreover, T antigen was able to reduce binding of p53-GAL4 to its GAL4 binding sequence in gel shift experiments in vitro. These observed activities of T antigen were all dependent upon a functional p53-binding domain. In addition, coexpression of human papillomavirus type 18 E6 protein, able to bind to p53, was able to significantly reduce p53-mediated transcription. These results suggest that an interaction of certain viral oncoproteins with p53 results in loss of transcriptional activity of p53, a function that is important for maintaining normal cell growth.
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PMID:SV40 T antigen abrogates p53-mediated transcriptional activity. 837 89

The E6 oncoproteins of the cancer-associated or high-risk human papillomaviruses (HPVs) target the cellular p53 protein. The association of E6 with p53 leads to the specific ubiquitination and degradation of p53 in vitro, suggesting a model by which E6 deregulates cell growth control by the elimination of the p53 tumor suppressor protein. Complex formation between E6 and p53 requires an additional cellular factor, designated E6-AP (E6-associated protein), which has a native and subunit molecular mass of approximately 100 kDa. Here we report the purification of E6-AP and the cloning of its corresponding cDNA, which contains a novel open reading frame encoding 865 amino acids. E6-AP, translated in vitro, has the following properties: (i) it associates with wild-type p53 in the presence of the HPV16 E6 protein and simultaneously stimulates the association of E6 with p53, (ii) it associates with the high-risk HPV16 and HPV18 E6 proteins in the absence of p53, and (iii) it induces the E6- and ubiquitin-dependent degradation of p53 in vitro.
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PMID:Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. 838 Aug 95

The protein encoded by the tumour-suppressor gene p53 can complex with SV40 virus large T antigen, the adenovirus E1B 58-kDa protein and the E6 protein of human papillomavirus type 16. The functions of these complexes are unclear, but there is some evidence to suggest that binding of p53 to these viral proteins may inactivate p53 function. Recent reports have shown that p53 is involved in regulation of transcription. We have considered the possibility that p53 may regulate transcription of viral genes important for virus replication and/or transformation. Inactivation of p53 function by formation of such complexes might then permit correct expression of these viral genes. Since p53 can bind to the SV40 virus enhancer/promoter, we have investigated the effect of p53 on transcription from this promoter and report here that mouse p53 is a potent repressor of the SV40 enhancer/promoter. Mutations within p53 severely inhibited this activity and provided some evidence to show that the N-terminus of p53 contains residues essential for this function. We also show that mouse p53 represses transcription from the promoters of viruses that do not express proteins that complex with p53: the human cytomegalovirus early promoter and the Rous sarcoma virus long terminal repeat. By studying the effect of p53 on transcription in different cell lines, we show that the effects of p53 on promoters may be cell type specific.
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PMID:Wild-type mouse p53 down-regulates transcription from different virus enhancer/promoters. 838 57

Infection with certain types of human papillomaviruses (HPV) is highly associated with carcinomas of the human uterine cervix. However, HPV infection alone does not appear to be sufficient for the process of malignant transformation, suggesting the requirement of additional cellular events. After DNA damage, normal mammalian cells exhibit G1 cell-cycle arrest and inhibition of replicative DNA synthesis. This mechanism, which requires wild-type p53, presumably allows cells to undertake DNA repair and avoid the fixation of mutations. We directly tested whether the normal response of cervical epithelial cells to DNA damage may be undermined by interactions between the E6 protein expressed by oncogenic HPV types and wild-type p53. We treated primary keratinocytes with the DNA-damaging agent actinomycin D and demonstrated inhibition of replicative DNA synthesis and a significant increase in p53 protein levels. In contrast, inhibition of DNA synthesis and increases in p53 protein did not occur after actinomycin D treatment of keratinocytes immortalized with HPV16 E6/E7 or in cervical carcinoma cell lines containing HPV16, HPV18, or mutant p53 alone. To test the effects of E6 alone on the cellular response to DNA damage, HPV16 E6 was expressed in the carcinoma cell line RKO, resulting in undetectable baseline levels of p53 protein and loss of the G1 arrest that normally occurs in these cells after DNA damage. These findings demonstrate that oncogenic E6 can disrupt an important cellular response to DNA damage mediated by p53 and may contribute to the subsequent accumulation of genetic changes associated with cervical tumorigenesis.
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PMID:Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. 838 5

Somatic mutations in the p53 tumor suppressor gene represent the single most common genetic alteration observed in human cancers. Interestingly, the great majority of malignant tumors of the cervix uteri contain wild-type p53 alleles together with the DNA of specific types of human papillomaviruses (HPVs), while the small portion of HPV-negative cervical carcinomas often carry alterations in the p53 tumor suppressor gene. Transcriptional activation of yet-undefined cellular regulatory genes has been implicated to play a key role for the tumor-suppressive activity of wild-type p53, as mutant p53 in general has lost the activity to stimulate p53-responsive reporter plasmids. The detection of DNA-binding-competent and transcriptionally active p53 protein in HeLa cervical carcinoma cells enabled us to investigate the in vivo effects of putative modulators on endogenous p53 function in cervical cancer cells. We show that the transcriptional stimulatory activity of HeLa cell p53 is strongly repressed by overexpression of E6 protein from oncogenic HPV type 16 (HPV16) but is not influenced by low-risk HPV6 E6. Similar to HPV16 E6, cellular oncoproteins such as mutant p53 or the product of the human mdm-2 gene also negatively interfere with p53-mediated transactivation in HeLa cells. Our findings indicate that, within a cervical cancer cell, the expression of E6 protein from high-risk HPV16, but not from low-risk HPV6, can lead to the same functional consequences as a mutation of the p53 gene. These results could provide a biochemical basis for the inverse correlation between the presence of HPV sequences and somatic mutations of the p53 gene in cervical carcinomas.
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PMID:Repression of endogenous p53 transactivation function in HeLa cervical carcinoma cells by human papillomavirus type 16 E6, human mdm-2, and mutant p53. 838 91


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