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

Genomic integrity is maintained by a network of cellular activities that assess the status of the genome at a given point in time, provide signals to proceed with or halt cell cycle progression, and provide for repair of damaged DNA. Mutations in any part of these pathways can have the ultimate effect of disturbing chromosomal integrity. Recent work suggests that p53 performs this integrator function in mammalian cells. Our present study demonstrates that in mortal cells, the expression of E6 and E7 viral oncoproteins of type 16 human papillomavirus each disrupts the integration of these signals by diverged pathways. Cells expressing E6 protein, which binds and degrades the p53 protein, exhibited alterations in cell cycle control when placed in drug and displayed the ability to amplify the CAD gene. The expression of E7, which binds different cellular proteins important for transformation, including Rb, led to a p53-independent alteration in cell cycle control, a widespread cytocidal response, and polyploidy as a mechanism of drug resistance. These results demonstrate that diverse perturbations of molecular pathways can have different effects on chromosomal integrity.
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PMID:Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. 792 57

The E6 protein of human papillomavirus (HPV) type 16 displays a number of activities when transfected into cultured cells, including transcriptional activation of several viral promoters and targeting of p53 for degradation. HPV 16E6 was found to function as a transcriptional repressor of the moloney murine leukemia virus long terminal repeat and the cytomegalovirus immediate early promoter. Although the degree of transcriptional repression was low, a dose-dependent two- to threefold decrease in promoter activity was consistently seen in cells expressing 16E6. HPV 16E6-dependent transcriptional repression was observed in C33a cells, which express mutant p53, and in Saos-2 cells, which lack p53. These results indicate that 16E6-dependent repression of promoter activity is unlikely to be mediated by p53.
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PMID:The E6 protein of human papillomavirus type 16 functions as a transcriptional repressor in a mechanism independent of the tumor suppressor protein, p53. 797 61

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

Epidemiological evidence suggests that alcohol intake, use of tobacco, ingestion of mycotoxins and nitrosamines and nutritional deficiencies are high-risk factors for the development of oesophageal cancer. Similarly, viral infections have been postulated to play a role in some tumours. However, the molecular events underlying the development of oesophageal carcinoma are poorly understood as yet. Loss of p53 tumour-suppressor gene function has been found in different human malignancies, and it can occur in a variety of ways, including gene mutation and interaction with the E6 protein of oncogenic human papillomaviruses (HPVs). Because the oesophageal mucosa is potentially exposed to mutagens and HPVs, we studied DNA samples derived from nine HPV-positive squamous cell carcinomas and 12 HPV-negative tumours. Exons 5-9 of the p53 gene containing phylogenetically conserved domains were examined using the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) technique. HPV detection was done using DNA in situ hybridisation with biotin-labelled HPV DNA probes. Mutations were detected in eight (38%) out of the 21 cases. Three mutations were found in exons 5/6, three in exon 7 and two in exon 8/9. Six (50%) of the 12 HPV-negative carcinomas showed p53 mutations. Two (22.2%) of the nine HPV-positive carcinomas were found to contain p53 mutations as well; one contained HPV 16 DNA sequences and showed p53 mutation in exon 8/9, and the other was HPV 6/11 positive with the mutation in exon 5/6. Although mutations were more common in HPV-negative tumours (50.0% vs 22.2%), the difference in p53 mutations in HPV-positive and -negative tumours did not reach statistical significance (P = 0.1946). These data indicate that inactivation of the p53 gene is a frequent event in oesophageal squamous cell carcinomas and such an inactivation might be an important molecular pathway for the development of oesophageal cancer. The findings of p53 mutations in HPV-positive oesophageal carcinomas suggest that HPV and p53 mutation were not mutually exclusive events. The presence of frequent mutations of p53 gene in both HPV-positive and -negative oesophageal carcinomas suggests a dominant role of environmental carcinogens in oesophageal carcinogenesis.
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PMID:Frequent mutations of p53 gene in oesophageal squamous cell carcinomas with and without human papillomavirus (HPV) involvement suggest the dominant role of environmental carcinogens in oesophageal carcinogenesis. 757 93

Functional p53 protein is associated with the ability of cells to arrest in G1 after DNA damage. The E6 protein of cancer-associated human papillomavirus type 16 (HPV-16) binds to p53 and targets its degradation through the ubiquitin pathway. To determine whether the ability of E6 to interact with p53 leads to a disruption of cell cycle control, mutated E6 proteins were tested for p53 binding and p53 degradation targeting in vitro, the ability to reduce intracellular p53 levels in vivo, and the ability to abrogate actinomycin D-induced growth arrest in human keratinocytes. Mutations scattered throughout the amino terminus, either zinc finger or the central region but not the carboxy terminus, severely reduced the ability of E6 to interact with p53. Expression of HPV-16 E6 or mutated E6 proteins that bound and targeted p53 for degradation in vitro sharply reduced the level of intracellular p53 induced by actinomycin D in human keratinocytes. A perfect correlation between the ability of E6 proteins to reduce the level of intracellular p53 and their ability to block actinomycin D-induced cellular growth arrest was observed. These results suggest that interaction with p53 is important for the ability of HPV E6 proteins to circumvent growth arrest.
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PMID:The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest. 805 51

Expression of the adenovirus E1A oncogene induces apoptosis which impedes both the transformation of primary rodent cells and productive adenovirus infection of human cells. Coexpression of E1A with the E1B 19,000-molecular-weight protein (19K protein) or the Bcl-2 protein, both of which have antiapoptotic activity, is necessary for efficient transformation. Induction of apoptosis by E1A in rodent cells is mediated by the p53 tumor suppressor gene, and both the E1B 19K protein and the Bcl-2 protein can overcome this p53-dependent apoptosis. The functional similarity between Bcl-2 and the E1B 19K protein suggested that they may act by similar mechanisms and that Bcl-2 may complement the requirement for E1B 19K expression during productive infection. Infection of human HeLa cells with E1B 19K loss-of-function mutant adenovirus produces apoptosis characterized by enhanced cytopathic effects (cyt phenotype) and degradation of host cell chromosomal DNA and viral DNA (deg phenotype). Failure to inhibit apoptosis results in premature host cell death, which impairs virus yield. HeLa cells express extremely low levels of p53 because of expression of human papillomavirus E6 protein. Levels of p53 were substantially increased by E1A expression during adenovirus infection. Therefore, E1A may induce apoptosis by overriding the E6-induced degradation of p53 and promoting p53 accumulation. Stable Bcl-2 overexpression in HeLa cells infected with the E1B 19K- mutant adenovirus blocked the induction of the cyt and deg phenotypes. Expression of Bcl-2 in HeLa cells also conferred resistance to apoptosis mediated by tumor necrosis factor alpha and Fas antigen, which is also an established function of the E1B 19K protein. A comparison of the amino acid sequences of Bcl-2 family members and that of the E1B 19K protein indicated that there was limited amino acid sequence homology between the central conserved domains of E1B 19K and Bcl-2. This domain of the E1B 19K protein is important in transformation and regulation of apoptosis, as determined by mutational analysis. The limited sequence homology and functional equivalency provided further evidence that the Bcl-2 and E1B 19K proteins may possess related mechanisms of action and that the E1B 19K protein may be the adenovirus equivalent of the cellular Bcl-2 protein.
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PMID:Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells. 808 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 E6 protein of the oncogenic human papillomavirus types 16 and 18 facilitates the rapid degradation of the tumor-suppressor protein p53 via the ubiquitin-dependent proteolytic pathway. The E6 protein binds to a cellular protein of 100 kDa termed E6-AP. The complex of E6 and E6-AP specifically interacts with p53 and induces the ubiquitination of p53 in a reaction which requires the ubiquitin-activating enzyme (E1) and a cellular fraction thought to contain a mammalian ubiquitin-conjugating enzyme (E2). This mammalian E2 activity could be replaced with bacterially expressed UBC8 from Arabidopsis thaliana, which belongs to a subfamily of E2s including yeast UBC4 and UBC5 which are highly conserved at the amino acid level. In this paper we describe the cloning of a human cDNA encoding a human E2 that we have designated UbcH5 and that is related to Arabidopsis UBC8 and the other members of this subfamily. We demonstrate that UbcH5 can function in the E6/E6-AP-induced ubiquitination of p53.
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PMID:Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. 809 Jul 26

The E6 protein encoded by human papillomavirus type 16 (HPV16), a genital virus with oncogenic potential, can target cellular p53 for rapid degradation following the formation of a complex including the two proteins. Some studies suggest that the E6 proteins encoded by HPV6 and 11, viral types which are normally limited to benign lesions, may also interact with p53, although the association is weaker than that seen with HPV16 E6. The present study demonstrates that E6 proteins from HPV16 and HPV6 can modulate the transcriptional regulatory functions of p53 in several cell types. A series of E6 mutants was used to show that association between E6 and p53 is necessary for this activity and that E6 proteins which retain the ability to associate with p53 but show no detectable degradation activity in vitro can, to some extent, abrogate p53 mediated transcriptional trans-regulation. This activity is augmented, however, by the ability of the E6 protein to target bound p53 for rapid degradation. These results suggest that some degree of modulation of p53 function is necessary in the normal viral life cycle but also demonstrate a correlation between the efficiency of this activity and oncogenic potential of the virus.
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PMID:Modulation of transcriptional regulatory properties of p53 by HPV E6. 813 25

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


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