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J. Biol. Chem., Vol. 280, Issue 24, 23094-23102, June 17, 2005

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Spatiotemporal Switch from Np73 to TAp73 Isoforms during Nephrogenesis

IMPACT ON DIFFERENTIATION GENE EXPRESSION^*

Zubaida Saifudeen, Virginia Diavolitsis, Jana Stefkova, Susana Dipp, Hao Fan, and Samir S. El-Dahr

From the Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

p73 is a member of the p53 gene family, which also includes p53 and p63. These proteins share sequence similarity and target genes but also have divergent roles in cancer and development. Unlike p53, transcription of the p73 gene yields multiple full-length (transactivation (TA) domain) and amino terminus-truncated (N) isoforms. Np73 acts in a dominant negative fashion to inhibit the actions of TAp73 and p53 on their target genes, promoting cell survival and proliferation and suppressing apoptosis. The balance between TAp73 and its negative regulator, Np73, may therefore represent an important determinant of developmental cell fate. There is little if anything known regarding the developmental regulation of the p73 gene. In this study, we showed that TAp73 and Np73 exhibit reciprocal spatiotemporal expression and functions during nephrogenesis. TAp73 was predominantly expressed in the differentiation domain of the renal cortex in an overlapping manner with the vasopressin-sensitive water channel aquaporin-2 (AQP-2). Chromatin immunoprecipitation assays demonstrated that the endogenous AQP-2 promoter was occupied by TAp73 in a developmentally regulated manner. Furthermore TAp73 stimulated AQP-2 promoter-driven reporter expression. TAp73 also activated the bradykinin B2 receptor (B2R) promoter, a developmentally regulated gene involved in regulation of sodium excretion. The transcriptional effects of TAp73 on AQP-2 and B2R were independent of p53. In marked contrast to TAp73, Np73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover Np73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from Np73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron.

Received for publication, December 27, 2004 , and in revised form, March 15, 2005.

^* This work was supported by grants from the National Institutes of Health (to S. S. E.-D. and Z. S.), the Society for Pediatric Research (to V. D.), and the American Heart Association, Southeast Affiliate (to H. F.). Digital images were obtained at Tulane Hypertension and Renal Center of Excellence Imaging Core Facility HEF2001-06-07 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.

To whom correspondence should be addressed: Dept. of Pediatrics, Tulane University Health Sciences Center, SL-37, 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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