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Molecular and Cellular Biology, February 2005, p. 1200-1212, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1200-1212.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Direct Intersection between p53 and Transforming Growth Factor ß Pathways Targets Chromatin Modification and Transcription Repression of the -Fetoprotein Gene

Deepti S. Wilkinson,^1, Stacey K. Ogden,^2,, Sabrina A. Stratton,^1, Julie L. Piechan,^2,¶ Thi T. Nguyen,¹ George A. Smulian,³ and Michelle Craig Barton^1*

Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biological Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas,¹ Department of Molecular Genetics, Biochemistry and Microbiology,² Infectious Disease Division, University of Cincinnati Medical Center, Cincinnati, Ohio³

Received 17 September 2004/ Returned for modification 25 October 2004/ Accepted 28 October 2004

We purified the oncoprotein SnoN and found that it functions as a corepressor of the tumor suppressor p53 in the regulation of the hepatic -fetoprotein (AFP) tumor marker gene. p53 promotes SnoN and histone deacetylase interaction at an overlapping Smad binding, p53 regulatory element (SBE/p53RE) in AFP. Comparison of wild-type and p53-null mouse liver tissue by using chromatin immunoprecipitation (ChIP) reveals that the absence of p53 protein correlates with the disappearance of SnoN at the SBE/p53RE and loss of AFP developmental repression. Treatment of AFP-expressing hepatoma cells with transforming growth factor-ß1 (TGF-ß1) induced SnoN transcription and Smad2 activation, concomitant with AFP repression. ChIP assays show that TGF-ß1 stimulates p53, Smad4, P-Smad2 binding, and histone H3K9 deacetylation and methylation, at the SBE/p53RE. Depletion, by small interfering RNA, of SnoN and/or p53 in hepatoma cells disrupted repression of AFP transcription. These findings support a model of cooperativity between p53 and TGF-ß effectors in chromatin modification and transcription repression of an oncodevelopmental tumor marker gene.

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

D.S.W., S.K.O., and S.A.S. contributed equally.

Present address: Dartmouth Medical School, Dept. of Pharmacology and Toxicology, Hanover, NH 03755.

^¶ Present address: Pfizer Global Research and Development, Department of CNS Pharmacology, Ann Arbor, MI 48105.

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