Transcriptional repression by wild-type p53 utilizes histone deacetylases,mediated by interaction with mSin3a

There is growing evidence that the p53 tumor suppressor protein not only ca n function to activate gene transcription but also to repress the expressio n of specific genes. Although recent studies have implicated the transcript ional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA ), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p 53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physica lly associates in vivo with HDACs. This interaction is not direct but, rath er, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, b ut not mutant p53, can be found bound to the Map4 promoter at times when th is promoter preferentially associates with deacetylated histones in vivo. S ignificantly, inhibition of p53-mediated transcriptional repression with TS A markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and unders core the importance of this activity for apoptosis induction by this protei n.