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 can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional 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 p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.
Murphy
M
M
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ME_Murphy@FCCC.edu
Ahn
J
J
Walker
K K
KK
Hoffman
W H
WH
Evans
R M
RM
Levine
A J
AJ
George
D L
DL
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors; D051379:Mice; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics; D016296:Mutagenesis; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D050777:Stathmin; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C493995:STMN1 protein, human; D050777:Stathmin; C493994:Stmn1 protein, mouse; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex