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

Human papillomavirus type 16 (HPV16) E6 and E7 are selectively retained and expressed in HPV16-associated human genital tumors. E6 is active in several cell culture assays, including transformation of NIH 3T3 cells, trans activation of the adenovirus E2 promoter, and cooperation with E7 to immortalize normal human keratinocytes. Biochemically, the HPV16 E6 protein has been shown to bind to tumor suppressor protein p53 in vitro and induce its degradation in a rabbit reticulocyte lysate. To examine the relationship between the various biological activities of E6 and inactivation of p53, we tested the abilities of dominant negative mutants of p53 to substitute functionally for E6 in the three cell culture assays. While wild-type p53 inhibited keratinocyte proliferation, both mouse and human mutant p53s, in conjunction with E7, increased proliferation of the keratinocytes, resulting in generation of immortalized lines. However, in contrast to E6, mutant p53 was unable to induce transformation or trans activate the adenovirus E2 promoter in NIH 3T3 cells. These results suggest that inactivation of wild-type p53 is necessary for HPV-induced immortalization of human keratinocytes and that different or additional activities are required for E6-dependent transformation and trans activation of NIH 3T3 cells.
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PMID:Mutant p53 can substitute for human papillomavirus type 16 E6 in immortalization of human keratinocytes but does not have E6-associated trans-activation or transforming activity. 131 1

The E6 and the E7 proteins of the oncogenic human papillomavirus types 16 and 18 can stably associate with p53 and the retinoblastoma protein, respectively. The E6-p53 interaction results in the accelerated degradation of p53 in vitro via the ubiquitin-dependent proteolysis system. In this study we demonstrate that a fusion protein consisting of the N-terminal half of the HPV-16 E7 protein and the full length HPV-16 E6 protein promotes the in vitro degradation of the retinoblastoma protein. This indicates that the property of the HPV-16 E6 protein to stimulate the degradation of p53 can be targeted to other proteins. Unlike the HPV-16 or HPV-18 E6 protein, the E6 proteins of HPV-6 and 11 do not bind to p53 and consequently do not target p53 for degradation. Analogous E7-E6 fusion proteins using the E6 proteins of HPV-6 and HPV-11, however, also have the ability to promote the degradation of the retinoblastoma protein, indicating that the property to target associated proteins for degradation is shared by the anogenital specific HPV E6 proteins.
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PMID:Targeted degradation of the retinoblastoma protein by human papillomavirus E7-E6 fusion proteins. 132 Oct 31

Little is known regarding the molecular genetic events in head and neck carcinoma. Epidemiological evidence suggests that both alcohol and tobacco use are related to the development of these neoplasms, and viral infections have also been postulated to play a role in some tumors. Loss of p53 tumor suppressor gene function has been found in many malignancies and can occur through either gene mutation or by interaction with the E6 protein of oncogenic human papilloma viruses (HPV). Because the mucosal surfaces of the head and neck are exposed to mutagens and HPVs, we studied DNA derived from 30 stage I-IV squamous cell carcinomas of the head and neck (9 primary tumors and 21 early passage cell lines) for p53 gene mutations as well as for the presence of oncogenic HPV DNA. Exons 2 through 11 of the p53 gene were examined using single strand conformation polymorphism analysis followed by direct genomic sequencing of all variants. HPV detection was done using polymerase chain reaction amplification with HPV E6 region type specific primers as well as L1 region degenerate ("consensus") primers; HPV type was determined by restriction fragment length polymorphism analysis of the amplified fragment as well as by Southern blotting of genomic DNA. Sixteen of 30 tumors (53%) had p53 mutations and oncogenic HPV DNA was detected in 3 of 30 (10%) tumors, none of which had p53 mutations. The p53 mutational spectrum observed was characterized by equal frequencies of transversions (6 of 16), transitions (5 of 16), and deletions (5 of 16). This distribution of mutations differs from the spectrum of p53 mutation reported in esophageal (P = 0.05) and lung (P = 0.02) cancers, two other tobacco associated neoplasms. A previously undescribed clustering of 3 mutations at codon 205 was also observed. A trend toward a shorter time to tumor recurrence after treatment was noted for those patients with tumors exhibiting p53 gene mutations, and no relationship between p53 mutations and tumor stage or node status was noted. Alteration in p53 gene function appears common in head and neck cancer, and the mutational spectrum observed may reflect the role of different mutagens or mutagenic processes than those responsible for the p53 mutations in lung and esophageal neoplasms.
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PMID:Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. 132 97

The p53 protein level was determined in normal oral keratinocytes and two non-tumorigenic, immortal oral keratinocyte lines harboring human papillomavirus-16 (HPV-16)DNA. The p53 mRNA level in the immortal cells was higher than the normal counterpart, but the p53 protein level was notably lower in the immortalised cells. The half-life of p53 protein in the normal and immortal cells was < 1 h, and the p53 cDNA sequence of these cells showed no mutation. The immortal cells transcribed a high amount of E6/E7 mRNA encoded by HPV-16, but normal cells did not. These observations suggest that the immortal keratinocytes may translate normal level of wild-type p53 protein, and the low p53 level in these cells may be due to the enhanced degradation of the protein by HPV-16 E6 protein.
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PMID:Low p53 level in immortal, non-tumorigenic oral keratinocytes harboring HPV-16 DNA. 133 28

We have shown previously that introduction of the human papillomavirus type 16 (HPV16) or HPV18 genome into human mammary epithelial cells induces their immortalization. These immortalized cells have reduced growth factor requirements. We report here that transfection with a single HPV16 gene E6 is sufficient to immortalize these cells and reduce their growth factor requirements. The RB protein is normal in these cells, but the p53 protein is sharply reduced, as shown by immunoprecipitation with anti-p53 antibody (pAB 421). We infer that the E6 protein reduces the p53 protein perhaps by signalling its destruction by the ubiquitin system. The HPV-transforming gene E7 was unable to immortalize human mammary epithelial cells. Thus, cell-specific factors may determine which viral oncogene plays a major role in oncogenesis.
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PMID:Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells. 165 67

The E6 protein of human papillomavirus types 16 and 18 (HPV-16 and HPV-18) can stably associate with the p53 protein in vitro. In the presence of rabbit reticulocyte lysate, this association leads to the specific degradation of p53 through the ubiquitin-dependent proteolysis system. We have examined the E6-p53 complex in more detail and have found that association of E6 with p53 is mediated by an additional cellular factor. This factor is present in rabbit reticulocyte lysate, primary human keratinocytes and in each of five human cell lines examined. The factor is designated E6-AP, for E6-associated protein, based on the observation that the E6 proteins of HPV-16 and 18 can form a stable complex with the factor in the absence of p53, whereas p53 association with the factor can be detected only in the presence of E6. Gel filtration and coprecipitation experiments indicate that E6-AP is a monomeric protein of approximately 100 kDa.
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PMID:A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. 166 71

Human papillomavirus type 16 (HPV-16) is a DNA tumor virus that is associated with human anogenital cancers and encodes two transforming proteins, E6 and E7. The E7 protein has been shown to bind to the retinoblastoma tumor suppressor gene product, pRB. This study shows that the E6 protein of HPV-16 is capable of binding to the cellular p53 protein. The ability of the E6 proteins from different human papillomaviruses to form complexes with p53 was assayed and found to correlate with the in vivo clinical behavior and the in vitro transforming activity of these different papillomaviruses. The wild-type p53 protein has tumor suppressor properties and has also been found in association with large T antigen and the E1B 55-kilodalton protein in cells transformed by SV40 and by adenovirus type 5, respectively, providing further evidence that the human papillomaviruses, the adenoviruses, and SV40 may effect similar cellular pathways in transformation.
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PMID:Association of human papillomavirus types 16 and 18 E6 proteins with p53. 215 86

The E6 protein encoded by the oncogenic human papillomavirus types 16 and 18 is one of two viral products expressed in HPV-associated cancers. E6 is an oncoprotein which cooperates with E7 to immortalize primary human keratinocytes. Insight into the mechanism by which E6 functions in oncogenesis is provided by the observation that the E6 protein encoded by HPV-16 and HPV-18 can complex the wild-type p53 protein in vitro. Wild-type p53 gene has tumor suppressor properties, and is a target for several of the oncoproteins encoded by DNA tumor viruses. In this study we demonstrate that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of p53. The E6-promoted degradation of p53 is ATP dependent and involves the ubiquitin-dependent protease system. Selective degradation of cellular proteins such as p53 with negative regulatory functions provides a novel mechanism of action for dominant-acting oncoproteins.
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PMID:The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. 217 76

To determine whether the dysfunction of p53 caused either by mutation of the p53 gene itself or by binding to E6 protein of oncogenic HPVs is involved in the transitional cell carcinomas (TCCs) of the bladder, we analyzed 23 TCCs of the bladder. DNA was extracted from each paraffin embedded tissue of TCCs of bladder and polymerase chain reaction (PCR)/single strand conformation polymorphism (SSCP) analysis were performed to screen mutations in p53 tumor suppressor gene, then PCR/dot blot hybridization were performed to detect infection of HPVs. We found that p53 gene mutation was found in 3 cases and oncogenic HPV infection was detected in 8 cases and thus, the overall incidence of possible p53 dysfunction was 47.8% on DNA analysis (If the results of immunohistochemistry to detect overexpression of p53 protein were included, the incidence was 60.9%). Therefore, we concluded that dysfunction of p53 plays a major role in the development of TCCs of bladder in Korean patients.
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PMID:Analysis of p53 tumor suppressor gene mutations and human papillomavirus infection in human bladder cancers. 748 75

The EBNA-LP protein (also known as EBNA-5) of Epstein-Barr virus (EBV) has been reported previously to colocalize in the nuclei of cells with the pRb protein and to bind in vitro to pRb and to the p53 protein, suggesting a role for EBNA-LP in modulation of the function of these proteins. Here we test in transfection assays whether EBNA-LP expression has any functional consequence for repression of E2F-1 activity by pRb or p107 or for activation of transcription by the p53 protein. No significant effect could be found, although the assay systems were sensitive to the established effects of simian virus 40 large T antigen and human papillo-mavirus type 16 E6 protein. There was very effective repression of GAL4/E2F-1 transactivation by p107, consistent with earlier reports and indicating that p107 can interact with the E2F-1 transactivation domain, even though p107 has been reported to bind specifically to E2F complexes containing E2F-4. The results indicate that, if the associations of EBNA-LP with pRB and p53 are physiologically relevant, they most likely affect other functions of these proteins or modulate their gene regulatory functions in ways that cannot be detected by transfection into cycling transformed cells.
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PMID:Epstein-Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays. 756 51


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