Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway

Mol Cell. 2010 Jun 11;38(5):700-11. doi: 10.1016/j.molcel.2010.05.020.

Abstract

The TIP60 tumor suppressor is a histone acetyltransferase involved in transcriptional regulation, checkpoint activation, and p53-directed proapoptotic pathways. We report that human papillomavirus (HPV) E6 destabilizes TIP60 both in vivo and in vitro. TIP60 binds to the HPV major early promoter and acetylates histone H4 to recruit Brd4, a cellular repressor of HPV E6 expression. Both low- and high-risk HPV E6 destabilize TIP60, thereby derepressing their own promoter. Destabilization of TIP60 by HPV E6 also relieves cellular promoters from TIP60-initiated repression and abrogates p53-dependent activation of apoptotic pathway. Degradation of TIP60, therefore, allows low- and high-risk HPV to promote cell proliferation and cell survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / physiology*
  • Cell Cycle Proteins
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lysine Acetyltransferase 5
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • PDZ Domains
  • Papillomavirus Infections / metabolism
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 18
  • E7 protein, Human papillomavirus type 18
  • Histones
  • Nuclear Proteins
  • Oncogene Proteins, Viral
  • Proteasome Inhibitors
  • Transcription Factors
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • UBE3A protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex