The HPV-16 E6 and E6-AP Complex Functions as a Ubiquitin-Protein Ligase in the Ubiquitination of p53

Cell. 1993 Nov 5;75(3):495-505. doi: 10.1016/0092-8674(93)90384-3.

Abstract

The ubiquitin-dependent proteolytic pathway plays a major role in selective protein degradation. Ubiquitination of proteins requires the sequential action of the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and in some cases ubiquitin-protein ligases (E3s). The oncogenic human papillomavirus (HPV) types 16 and 18 utilize this cellular proteolytic system to target the tumor suppressor protein p53. The HPV E6 oncoprotein binds to a cellular protein of 100 kd, termed E6-associated protein (E6-AP). The E6-E6-AP complex specifically interacts with p53, resulting in the rapid ubiquitin-dependent degradation of p53. Here we report the purification and identification of the factors necessary for the E6-E6-AP-mediated ubiquitination of p53. The ubiquitination of p53 requires the E1 enzyme and a novel E2 in mammalian cells, while E3 activity is conferred by the E6-E6-AP complex. Furthermore, E6-AP appears to have ubiquitin-protein ligase activity in the absence of E6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Ligases / isolation & purification
  • Ligases / metabolism*
  • Macromolecular Substances
  • Models, Biological
  • Oncogene Proteins, Viral / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquinone / metabolism*
  • Ubiquitin-Activating Enzymes
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Viral Proteins / metabolism*

Substances

  • E6 protein, Human papillomavirus type 16
  • Macromolecular Substances
  • Oncogene Proteins, Viral
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Viral Proteins
  • Ubiquinone
  • Ubiquitin-Conjugating Enzymes
  • UBE3A protein, human
  • Ubiquitin-Protein Ligases
  • Ligases
  • Ubiquitin-Activating Enzymes