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J. Biol. Chem., Vol. 281, Issue 42, 31234-31244, October 20, 2006

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The Polycystic Kidney Disease-1 Gene Is a Target for p53-mediated Transcriptional Repression^*

Diederik Van Bodegom, Zubaida Saifudeen, Susana Dipp, Sanjeev Puri, Brenda S. Magenheimer, James P. Calvet, and Samir S. El-Dahr¹

From the Departments of Pediatrics and Physiology, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112 and the Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160

This study provides evidence that the tumor suppressor protein, p53, is a transcriptional repressor of PKD1. Kidneys of p53-null mice expressed higher Pkd1 mRNA levels than wild-type littermates; -irradiation suppressed PKD1 gene expression in p53^+/+ but not p53^–/– cells; and chromatin immunoprecipitation assays demonstrated the binding of p53 to the PKD1 promoter in vivo. In transient transfection assays, p53 repressed PKD1 promoter activity independently of endogenous p21. Deletion analysis mapped p53-mediated repression to the proximal promoter region of PKD1. Mutations of the DNA binding or C-terminal minimal repression domains of p53 abolished its ability to repress PKD1. Moreover, trichostatin A, an inhibitor of histone deacetylase activity, attenuated p53-induced repression of the PKD1 promoter. These findings, together with previous reports showing that dedifferentiated Pkd1-deficient cells express lower p53 and p21 levels, suggest a model whereby PKD1 signaling activates the p53-p21 differentiation pathway. In turn, p53 cooperates with histone deacetylases to repress PKD1 gene transcription. Loss of a p53-mediated negative feedback loop in PKD1 mutant cells may therefore contribute to deregulated PKD1 expression and cystogenesis.

Received for publication, July 10, 2006 , and in revised form, August 21, 2006.

^* This work was supported by National Institutes of Health Grants DK-57301 (to J. P. C.), DK-56264, and DK-62250 (to S. S. E.), the Tulane Hypertension and Renal Center of Excellence, and Louisiana Board of Regents, through the Millennium Trust Health Excellence Fund. 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 To whom correspondence should be addressed: Dept. of Pediatrics, SL-37, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112. Tel.: 504-988-5377; Fax: 504-988-1852; E-mail: seldahr{at}tulane.edu.

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