Function of Wild-type and Mutant Forms of p53 in Breast Cancer.
Final rept. 1 Aug 94-31 Jul 97
COLUMBIA UNIV NEW YORK
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The p53 tumor suppressor protein is a transcriptional activator and its transcriptional activity is required for p53 tumor suppression. We show here that p53 markedly activates expression of cyclin DI and the induction of cyclin Dl is at least partially mediated by p21, a target of p53. To further understand features of p53 that contribute to cell cycle arrest and apoptosis several p53-null cell lines were generated that inducibly express wild-type or mutant forms of p53. Our results show that the cellular level of p53 can dictate the response of the cell to undergo either cell cycle arrest or apoptosis and DNA damage can heighten the apoptotic response to p53. We also demonstrate that a full apoptotic response to pS3 requires both its N- and C-termini. In addition, we identify a novel activity within amino acids 43-63 which can activate transcription and mediate apoptosis. Furthermore, we show that the N-terminus of p53 is the target for destabilization mediated by ubiquitin and calpaln and phosphorylation at serine 15 is in part attributable to stabilization following DNA damage.
- Medicine and Medical Research