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Molecular and Cellular Biology, March 2008, p. 1988-1998, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01442-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression{triangledown} ,{dagger}

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, Texas 77030

Received 10 August 2007/ Returned for modification 24 September 2007/ Accepted 7 January 2008

In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, 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 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 β (TGF-β) responses, we find that SnoN actively participates in AFP 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 marker AFP and reestablish transcription repression.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Unit 1000, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 834-6268. Fax: (713) 834-6273. E-mail: mbarton{at}mdanderson.org

{triangledown} Published ahead of print on 22 January 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2008, p. 1988-1998, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01442-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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