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Mol. Cell. Biol. doi:10.1128/MCB.01442-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer TGF{beta}-mediated transcription repression

Deepti Srinivas Wilkinson, Wen-Wei Tsai, Maria A. Schumacher, and Michelle Craig Barton*

Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

* To whom correspondence should be addressed. Email: mbarton{at}mdanderson.org.


  Abstract

In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an onco-developmental 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 co-repressor mSin3A to the AFP distal promoter. Sequential ChIP 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 TGF{beta}-responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF{beta}-signaling restores a dynamic interplay between p53 and TGF{beta}-effectors that cooperate to effectively target mSin3A to tumor marker AFP and re-establish transcription repression.




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