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Originally published In Press as doi:10.1074/jbc.M009056200 on February 20, 2001

J. Biol. Chem., Vol. 276, Issue 20, 16817-16823, May 18, 2001
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The Human Sex-determining Gene SRY Is a Direct Target of WT1*

Anwar Hossain and Grady F. SaundersDagger

From the Department of Biochemistry and Molecular Biology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The product of the Wilms' tumor gene, WT1, is essential for male sex determination and differentiation in mammals. In addition to causing Wilms' tumor, mutations in WT1 often cause two distinct but overlapping urogenital defects in men, Denys-Drash syndrome and Frasier syndrome. In this study we investigated the regulation of the sex determination gene SRY by WT1. Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA-binding sequences in the core promoter. Mutant WT1 proteins in Denys-Drash syndrome patients were unable to activate this promoter. These mutants did not act in a dominant negative manner, as expected over the wild-type WT1 in this promoter. We also found that WT1 could transactivate the endogenous SRY gene. These observations, together with the overlapping expression patterns of WT1 and SRY in human gonads, led us to propose that WT1 regulates SRY in the initial sex determination process in humans and activates a cascade of genes ultimately leading to the complete organogenesis of the testis.

* This work was supported by National Institutes of Health Grants CA 34936 and CA 16672.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Box 117, the University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-2690; Fax: 713-791-9478; E-mail: gsaunders@odin.mdacc.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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