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J. Biol. Chem., Vol. 280, Issue 47, 39152-39160, November 25, 2005

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Family Members p53 and p73 Act Together in Chromatin Modification and Direct Repression of -Fetoprotein Transcription^*

Rutao Cui12, Thi T. Nguyen1, Joseph H. Taube1, Sabrina A. Stratton, Miriam H. Feuerman, and Michelle Craig Barton3

From the Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biological Sciences, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and the Department of Biochemistry, State University of New York Downstate Medical Center, Brooklyn, New York 11203

Aberrant expression of the -fetoprotein (AFP) gene is a diagnostic tumor marker of hepatocellular carcinoma. We find that AFP gene expression is repressed by the TP53 family member p73 during normal hepatic development and when p73 or p73 is introduced into cultured hepatoma cells that express AFP. Transient co-transfection of p53 family members showed that p53 and transactivating (TA)-p73, but not TA-p63, repress endogenous AFP transcription additively or independently. p53-independent functions of p73 are further supported by delayed, p73-associated compensation of AFP repression during development of the p53-null mouse. Chromatin immunoprecipitation assays of normal and p53-null mouse liver tissue showed that TA-p73 binds at a previously identified p53 repressor site (-860/-830) within the distal promoter of AFP at a level equivalent to p53 in wild type liver, with increased binding of TA-p73 to chromatin in the absence of p53. Sequential chromatin immunoprecipitation analyses revealed that TA-p73 and p53 bind simultaneously to their shared regulatory site in wild type liver. Like the founding family member p53, TA-p73 represses AFP expression by chromatin structure alteration, targeting reduction of acetylated histone H3 lysine 9 and increased dimethylated histone H3 lysine 9 levels. However, chromatin-bound TA-p73 is associated with elevated di- and tri-methylated histone H3 lysine 4 levels in p53-null liver and hepatoma cells, concomitant with a reduced ability to repress transcription compared with p53.

Received for publication, April 28, 2005 , and in revised form, September 28, 2005.

^* This work was supported by Grant GM53683 from the National Institutes of Health (to M. C. B.) and in part by an NCI (National Institutes of Health) Cancer Center Support Grant to the University of Texas M. D. Anderson Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Pediatric Oncology Dept., Dana Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, Massachusetts 02115.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 117, Houston, TX 77030. Tel.: 713-834-6268; Fax: 713-834-6273; E-mail: mbarton{at}odin.mdacc.tmc.edu.

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