title: Sensitivity of p53 lysine mutants to ubiquitin-directed degradation targeted by human papillomavirus E6.
abstract: The activity of the p53 tumor suppressor protein is regulated, at least in part, through the stability of the protein. p53 degradation in normal cells is controlled by ubiquitin-dependent proteolysis, and activation of p53 following DNA damage is associated with an increase in the stability of the protein. The human papillomavirus-encoded E6 protein abrogates p53 function by targeting it for rapid degradation, also through the ubiquitin pathway. Although the p53 protein is ubiquitinated following interaction with E6, we show here that none of the lysine residues within p53 are specifically required for E6-targeted degradation. Mutation of lysine residues within the C-terminus of p53 resulted in resistance to E6-mediated degradation in vitro, although the ability of the two proteins to form a complex was not affected. The same mutant was efficiently targeted for degradation in cells, however, illustrating a lack of correlation between the in vitro and the in vivo assays.
authors.affiliation: Institute of Cancer Research, Haddow Laboratories, Sutton, United Kingdom.
authors.forename: T
authors.initials: T
authors.lastname: Crook
authors.forename: R L
authors.initials: RL
authors.lastname: Ludwig
authors.forename: N J
authors.initials: NJ
authors.lastname: Marston
authors.forename: D
authors.initials: D
authors.lastname: Willkomm
authors.forename: K H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D011485:Protein Binding; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D004247:DNA; D008239:Lysine