Open AccessChromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression
Author(s) -
Deepti Srinivas Wilkinson,
Wen Wei Tsai,
Maria A. Schumacher,
Michelle C. Barton
Publication year - 2008
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01442-07
Subject(s) - corepressor , psychological repression , biology , smad , chromatin immunoprecipitation , transcription factor , chromatin , transcription (linguistics) , microbiology and biotechnology , repressor , transforming growth factor beta , transforming growth factor , cancer research , promoter , gene , genetics , gene expression , linguistics , philosophy
In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription ofAFP , an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to theAFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression ofAFP transcription. In addition to its well-known function in antagonizing transforming growth factor β (TGF-β) responses, we find that SnoN actively participates inAFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-β signaling restores a dynamic interplay between p53 and TGF-β effectors that cooperate to effectively target mSin3A to tumor markerAFP and reestablish transcription repression.