SENSITIVITY OF P53 LYSINE MUTANTS TO UBIQUITIN-DIRECTED DEGRADATION TARGETED BY HUMAN PAPILLOMAVIRUS E6

The activity of the p53 tumor suppressor protein is regulated, at leas t in part, through the stability of the protein. p53 degradation in no rmal cells is controlled by ubiquitin-dependent proteolysis, and activ ation of p53 following DNA damage is associated with an increase in th e stability of the protein. The human papillomavirus-encoded E6 protei n abrogates p53 function by targeting it for rapid degradation, also t hrough the ubiquitin pathway. Although the p53 protein is ubiquitinate d following interaction with E6, we show here that none of the lysine residues within p53 are specifically required for E6-targeted degradat ion. Mutation of lysine residues within the C-terminus of p53 resulted in resistance to E6-mediated degradation in vitro, although the abili ty of the two proteins to form a complex was not affected. The same mu tant was efficiently targeted for degradation in cells, however, illus trating a lack of correlation between the in vitro and the in vivo ass ays. (C) 1996 Academic Press, Inc.