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

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

The HPVs associated with anogenital cancers encode two oncoproteins, E6 and E7. Both E6 and E7 can form specific complexes with tumour suppressor gene products. The E7 protein binds to the retinoblastoma tumour suppressor gene product pRB, with a preference for the underphosphorylated, "active" form of pRB. The E7 proteins derived from the "high risk" HPVs bind to pRB with a higher affinity than the E7 proteins from the "low risk" HPVs. The "high risk" HPV E6 proteins can associate with the p53 tumour suppressor protein. This interaction promotes the degradation of p53 in vitro, which presumably accounts for the very low levels of p53 in cervical carcinoma cell lines. The functional inactivation of pRB and p53 by the HPV oncoproteins E7 and E6, respectively, are likely to be important steps in cervical carcinogenesis, since mutations in the RB and p53 genes were detected in HPV negative but not HPV positive cervical carcinoma cell lines. Cytogenetic studies strongly suggest, however, that additional chromosomal changes may be necessary for carcinogenic progression of HPV induced anogenital lesions.
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PMID:Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. 132 42

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

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

We previously immortalized normal human oral keratinocytes by transfection with recombinant HPV-16 DNA and subsequently exposed the cells to benzo(a)pyrene for 7 days. The exposure to benzo(a)pyrene modified the immortalized cells: the modified cells (HOK-16B-BaP) proliferated in an ordinary culture medium containing physiological calcium level (1.5 mM), but demonstrated only enhanced proliferation capacity without tumor formation in nude mice and failed to show in vitro anchorage-independency. In this study, we further modified the HOK-16B-BaP cells by subculturing the cells in a medium containing benzo(a)pyrene for 6 months. The cells were further modified with a chronic benzo(a)pyrene exposure and were termed HOK-16B-BaP-T cells (1) demonstrated a malignant phenotype in organotypic 'raft' culture, (2) showed in vitro anchorage-independency, (3) developed tumors in nude mice when injected subcutaneously, (4) contained a significantly higher copy number of intact and integrated HPV-16 DNA; (5) contained higher level of HPV-16 E6/E7 messages and E7 protein, (6) were more resistant to transforming growth factor-beta 1 and (7) secreted higher level of vascular endothelial growth factor with molecular weight of 56 kd than parental HOK-16B-BaP cells. However, the levels of p53 and ras proteins and the levels of p53, c-myc and c-fos transcripts in the HOK-16B-BaP-T cells were not different from those in the HOK-16B-BaP cells. The highly conserved coding regions of the p53, c-Ha-ras1, and c-Ki-ras2 genes of the tumor cells were not mutated. These data indicate that the HPV-immortalized human oral keratinocytes can convert to tumorigenic cells by chronic exposure to benzo(a)pyrene. The tumorigenic conversion seems to be associated with (1) the overexpression of viral oncogenes such as E6 and E7 genes, (2) the higher resistance of cells to transforming growth factor-beta 1 and (3) the high secretion of 56 kd vascular endothelial growth factor from the cells.
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PMID:Combined oral carcinogenicity of HPV-16 and benzo(a)pyrene: an in vitro multistep carcinogenesis model. 778 58

The E6 and the E7 genes of the high-risk types of human papillomavirus (types 16 and 18) are associated with the induction or maintenance of malignant growth. The molecular mechanism by which these oncogenes contribute to the malignant phenotype is not clear. To study the effects of E7 on cellular processes, we constructed a stable cell line that inducibly expressed the E7 gene of HPV16. By using this cell line, we provide evidence that expression of E7 of HPV16 stimulates c-fos gene expression. Also, by doing transient transfection experiments, we show that the expression of either E6 or E7 induces transcription from the c-fos promoter. Analysis of a series of c-fos promoter mutants indicates that the activation by both E6 and E7 is dependent on the cyclic AMP response element. To further investigate the mechanism(s) of the activation of the c-fos gene and their relation to the oncogenic properties of E6 and E7, several mutants of the E6 and E7 genes were analyzed. The results of these studies indicate that the CR1 and CR2 regions in the E7 protein, and sequences distinct from the p53-binding region in the E6 protein, are critical for activation of the c-fos promoter.
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PMID:Activation of the c-fos gene by the HPV16 oncoproteins depends upon the cAMP-response element at -60. 803 92

The points of this presentation are reform of the theory relating to "Dysplasia and Carcinogenesis" and the cytological methods. In 1976, Meisels and Fortin reported that dysplasia is the disease caused by Human papilloma virus (HPV), and surprisingly, intermediate cells infected by HPV possessed the ability of proliferation and mitosis, resulting in binucleation and multinucleation. In cytology, dysplasia is thought to be delivered from basal cells and abnormal cells are differentiated from lower layer to upper layer, the grade of dysplasia is judged from the level of cell-differentiation. In histology, however, differentiated cells are thought to be normal cells from the histological definition. Therefore, the histological theory cannot explain the fact that the appearance of the abnormal cells from the all layers in cytology of the mild dysplasia. This discrepancy can be understood well if we think it is caused by HPV infection. HPV (ds-DNA) can only proliferate using cellular factors. And as keratinocytes is important with relating to this proliferation, HPV affects human intermediate layer and upper layer. In HPV-infected cells, HPV-E6 protein and E7 protein can bind the products of p53 and pRB, suppressor genes, respectively. These lead to degradation of these proteins' function, acceleration of cell proliferation, and abnormality of cell-cycle time. Our fundamental theory of dyskaryosis is based on these findings. Mild dysplasia is transferred from intermediate layer to upper layer and vanish after cell maturation. Immortalization, transformation, and gene alteration are important factors for carcinogenesis. The deletion of chromosome 3p is one of the most important genetic changes during carcinogenesis. On the basis of carcinogenesis theory described above, the cytological findings of HPV-infected cells are classified into three steps.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Gynecological cytology in theory and practice]. 808 7

The transforming genes E6 and E7 of high-risk human papillomaviruses are consistently expressed in papillomavirus-associated neoplasms of the anogenital tract. In papillomavirus type 18-associated SW 756 cervical carcinoma cells, transcription of the viral E6-E7 genes is blocked by dexamethasone. Herein we show that dexamethasone-mediated repression of the E6-E7 genes results in loss of the neoplastic phenotype of SW 756 cells. Withdrawal of dexamethasone restores E6-E7 expression and neoplastic growth. Moreover, reconstitution of E6-E7 gene expression by a dexamethasone-inducible expression vector renders the neoplastic phenotype resistant to dexamethasone. These results clearly indicate that the continuous expression of the viral E6-E7 oncogenes is required to maintain the neoplastic growth properties of SW 756 cervical cancer cells. The viral E6 protein destabilizes the p53 tumor suppressor gene product in vitro. Since low levels of p53 have been observed in papillomavirus-transformed keratinocyte cell lines, it was speculated that degradation of p53 by E6 contributes to papillomavirus-associated growth deregulation. Consistent with this hypothesis, we detected a significant increase in p53 levels upon dexamethasone-induced repression of papillomavirus E6-E7 oncogene expression. No p53 increase was observed in dexamethasone-treated cells in which the viral oncogene expression was restored. The viral E7 protein has been shown to complex with the retinoblastoma tumor suppressor gene product (pRB). In some cells, this interaction has been shown shown to release the transcription factor E2F from its complex with pRB, and it has been hypothesized that E7-induced, increased levels of free E2F contribute to the transforming potential of the viral oncogenes. In gel shift experiments, we detected relatively stable complexes of pRB and E2F in all SW 756-derived cells, independent of the level of E7 expression. This suggests that E7-mediated release of E2F from its complex with pRB might not be required to maintain the neoplastic phenotype of human papillomavirus-associated cancer cells, although a possibly relevant partial E7-mediated release of E2F from pRB cannot be excluded.
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PMID:Reversible repression of papillomavirus oncogene expression in cervical carcinoma cells: consequences for the phenotype and E6-p53 and E7-pRB interactions. 815 52

The tumor suppressor genes p53, Rb, and DCC were studied in five human oral cancer cell lines (FaDu, SCC-4, HEp-2, 1483, and OEC-M1) and in primary normal human oral keratinocytes (NHOK). All tested cancer lines had similar amount of p53 messages to normal cells, but the cancer lines FaDu and SCC-4 contained significantly higher p53 protein levels than did the normal counterpart. Sequencing p53 cDNA for these cancer cells showed point mutations: In the FaDu cell line, a mutation of CGG to CTG occurred at codon 248; and in the SCC-4 cell line, a mutation of CCC to TCC occurred at codon 151. The HEp-2 and 1483 cancer lines translated very low levels of p53 protein compared to the normal counterpart. Sequencing of p53 cDNA for HEp-2 and 1483 lines showed no mutations. Southern and Northern analyses revealed that these cell lines harbored HPV-18 DNA and expressed the viral E6/E7 protein. The OEC-M1 line showed different restriction fragment length polymorphism for the p53 gene compared with other cells, and did not express p53. All oral cancer cell lines except the OEC-M1 cells expressed both phosphorylated and hypophosphorylated Rb proteins. Further, the OEC-M1 line expressed smaller sized hypophosphorylated Rb proteins compared with normal cells. Unlike the other cancer lines, the HEp-2 and OEC-M1 lines also did not contain DCC mRNAs. These data indicate that "high risk" HPV infections and mutations of p53, Rb, and DCC genes are frequently found in oral cancer cells and may be associated with oral cancer.
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PMID:State of p53, Rb and DCC tumor suppressor genes in human oral cancer cell lines. 823 12

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


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