Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor (cid:2) -Mediated Transcription Repression (cid:1) †

In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP , an oncode-velopmental 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 the AFP 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 of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor (cid:1) (TGF- (cid:1) ) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF- (cid:1) signaling restores a dynamic interplay between p53 and TGF- (cid:1) effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.

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