Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription

Mark S. Lechner, David H. Mack, Angela B. Finicle, Tim Crook, Karen H. Vousden, Laimonis A. Laimins

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

The transforming proteins of DNA tumor viruses SV40, adenovirus and human papillomaviruses (HPV) bind the retinoblastoma and p53 cell cycle regulatory proteins. While the binding of SV40 large T antigen and the adenovirus E1B 55 kDa protein results in the stabilization of the p53 protein, the binding of HPV16 and 18 E6 results in enhanced degradation in vitro. To explore the effect of viral proteins on p53 stability in vivo, we have examined cell lines immortalized in tissue culture by HPV18 E6 and E7 or SV40 large T antigen, as well as cell lines derived from cervical neoplasias. The half-life of the p53 protein in non-transformed human foreskin keratinocytes in culture was found to be 3 h while in cell lines immortalized by E6 and E7, p53 protein half-lives ranged from 2.8 h to < 1 h. Since equivalent levels of E6 were found in these cells, the range in p53 levels observed was not a result of variability in amounts of E6. In keratinocyte lines immortalized by E7 alone, the p53 half-life was found to be similar to that in non-transformed cells; however, it decreased to ~ 1 h following supertransfection of an E6 gene. These observations are consistent with an interaction of E6 and p53 in vivo resulting in reductions in the stability of p53 ranging between 2- and 4-fold. We also observed that the expression of various TATA containing promoters was repressed in transient assays by co-transfection with plasmids expressing the wild-type p53 gene. The inclusion of human papillomavirus E6 or SV40 T antigen expression plasmids in these transfection assays abrogated p53-mediated repression, demonstrating that these oncoproteins can modulate p53 function in vivo. Mutant E6 proteins that bind p53 but fail to stimulate degradation retained the ability to relieve repression, while no such effect was observed with E6 mutants that were unable to bind p53. These studies demonstrate that E6 and p53 interact in vivo and suggest that E6 binding alone can modulate the transcriptional inhibitory effects of p53.

Original languageEnglish (US)
Pages (from-to)3045-3052
Number of pages8
JournalEMBO Journal
Volume11
Issue number8
DOIs
StatePublished - 1992

Keywords

  • E6
  • HPV
  • Repression
  • Transormation
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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