The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53

Scheffner, Martin; Werness, Bruce A.; Huibregtse, Jon M.; Levine, Arnold J.; Howley, Peter M.

doi:10.1016/0092-8674(90)90409-8

Cited by 3,697 publications

(2,681 citation statements)

References 45 publications

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“…Later, it was discovered that viral oncoproteins from other DNA tumour viruses have the properties to bind p53. Thus the adenovirus E1B (Sarnow et al, 1982) and human papillomavirus HPV E6 protein (Sche ner et al, 1990), Epstein ± Barr virus nuclear antigen (Szekely et al, 1993), hepatitis B virus X protein and human cytomegalovirus IE84 protein (Speir et al, 1994), form complexes with the p53 protein.…”

Section: Early Studies Indicate a Role Of P53 In Cell Transformationmentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

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Section: Early Studies Indicate a Role Of P53 In Cell Transformationmentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

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“…Therefore, we estimated that 20% red colonies should be acceptable and clinically safe cut-o point for detecting p53 mutation without sequencing analysis. It is known that transactivation function of the p53 protein is abrogated not only by intragenic mutations of p53 but also by complex formation with oncogenic HPV E6 protein (Sche ner et al, 1990). We detected the presence of HPV-16 E6 mRNA in one of seven p53 mutation-negative samples.…”

Section: Discussionmentioning

confidence: 81%

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

et al. 1997

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To determine the timing and actual incidence of p53 mutations in oral epithelial lesions, we examined 33 primary squamous cell carcinomas (SCCs), 14 dysplasias and six hyperplasias from Japanese patients by a combination of yeast functional assay and DNA sequencing. The assay detects mutations of p53 mRNA between codons 67 and 347 on the basis of the DNAbinding activity of the protein. Twenty-six SCCs (79%) and ®ve dysplasias (36%) were positive for p53 mutation, while all six hyperplasias were negative for the mutation. Human papillomavirus type 16 E6 mRNA was detected in one of seven p53 mutation-negative SCCs by reverse transcription polymerase chain reaction (RT ± PCR). We further examined p53 mutations in 17 Sri Lankan oral SCCs using the yeast functional assay and the singlestrand conformation polymorphism analysis of PCRampli®ed DNA fragments (PCR ± SSCP) of exon 5 ± 8. The mutations were con®rmed by DNA sequencing and the detection sensitivity was compared between the two methods. Six samples (35%) were positive for p53 mutation in PCR ± SSCP analysis, while nine samples (53%) were positive in yeast functional assay. This suggests that the incidence of p53 mutations has been considerably underestimated in the conventional SSCP analysis. The present data indicate that p53 mutations are extremely frequent in oral cancers in the Japanese, and suggest that the timing and signi®cance of p53 mutation in oral tumor progression vary in di erent ethnic populations and areas.

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“…Our identification of astrocytoma cases with high immunostaining scores, in the absence of mutations in coding sequences of the p53 gene, suggests that p53 may act through downstream mechanisms that are distinct from purely tumour-suppressive functions in its native form, or as a dominant-negative regulator in mutant or oncogenic forms. Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins were identified and found to be potential oncogenes (Scheffner et al, 1990;Bargonetti et al, 1991;Debbas and White, 1993;Nees et al, 2001;Cobbs et al, 2003;Dai et al, 2003;Calogero et al, 2004). Proteins implicated in cell cycle regulation may serve as downstream effectors of p53 function (Dulic et al, 1994;Agarwal et al, 1995;de Toledo et al, 1998;Skomedal et al, 1999;Ghimenti et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Early studies suggested that p53 abnormalities contribute to the development of malignant transformation in astrocytic brain tumours (Frankel et al, 1992;Sidransky et al, 1992). Loss of heterozygosity on human chromosome 17p, 53 point mutations, and altered p53 expression were reported in astrocytomas (Scheffner et al, 1990;Werness et al, 1990;Fujimaki et al, 1991;Lowe and Ruley, 1993;Chozick et al, 1994a;Iuzzolino et al, 1994;Slebos et al, 1994;Morita et al, 1996;Sarkar et al, 2002). Our goal is to assess the significance of potential alterations in p53 protein expression, and its interrelationship with more traditional prognostic factors in astrocytoma tumour progression, in rigorous fashion.…”

mentioning

confidence: 99%

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Pardo

Hsu

Zeheb³

et al. 2004

Br J Cancer

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Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (Po0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

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The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53

Cited by 3,697 publications

References 45 publications

Twenty years of p53 research: structural and functional aspects of the p53 protein

Twenty years of p53 research: structural and functional aspects of the p53 protein

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

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