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J. Biol. Chem., Vol. 282, Issue 7, 5026-5036, February 16, 2007

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Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology^*

Weidong Yong¹, Zuocheng Yang¹, Sumudra Periyasamy^¶, Hanying Chen, Selcul Yucel^||, Wei Li, Leanne Y. Lin, Irene M. Wolf^¶, Martin J. Cohn^**, Laurence S. Baskin^||, Edwin R. Sánchez^¶, and Weinian Shou²

From the Herman B. Wells Center for Pediatric Research, Section of Pediatric Cardiology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Pediatrics, Third Xiang-Ya Hospital, Central South University, Xiang-Ya School of Medicine, Changsha 410013, China, the ^¶Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio 43614, the ^||Department of Urology, University of California School of Medicine, San Francisco, California 94143, and the ^**Department of Zoology, University of Florida, Gainesville, Florida 32611

Fkbp52 and Fkbp51 are tetratricopeptide repeat proteins found in steroid receptor complexes, and Fkbp51 is an androgen receptor (AR) target gene. Although in vitro studies suggest that Fkbp52 and Fkbp51 regulate hormone binding and/or subcellular trafficking of receptors, the roles of Fkbp52 and Fkbp51 in vivo have not been extensively investigated. Here, we evaluate their physiological roles in Fkbp52-deficient and Fkbp51-deficient mice. Fkbp52-deficient males developed defects in select reproductive organs (e.g. penile hypospadias and prostate dysgenesis but normal testis), pointing to a role for Fkbp52 in AR-mediated signaling and function. Surprisingly, ablation of Fkbp52 did not affect AR hormone binding or nuclear translocation in vivo and in vitro. Molecular studies in mouse embryonic fibroblast cells uncovered that Fkbp52 is critical to AR transcriptional activity. Interestingly, Fkbp51 expression was down-regulated in Fkbp52-deficient males but only in affected tissues, providing further evidence of tissue-specific loss of AR activity and suggesting that Fkbp51 is an AR target gene essential to penile and prostate development. However, Fkbp51-deficient mice were normal, showing no defects in AR-mediated reproductive function. Our work demonstrates that Fkbp52 but not Fkbp51 is essential to AR-mediated signaling and provides evidence for an unprecedented Fkbp52 function, direct control of steroid receptor transcriptional activity.

Received for publication, October 3, 2006 , and in revised form, December 1, 2006.

^* This study was supported in part by National Institutes of Health Grants DK73402 (to W. S. and E. S), DK70127 (to E. S. and W. S.), and DK43867 (to E. S.) and the Riley Children's Foundation (to W. S.). 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 To whom correspondence should be addressed: Herman B. Wells Center for Pediatric Research, R4-368, 1044 W. Walnut, Indianapolis, IN 46202. Tel.: 317-274-8952; Fax: 317-278-5413; E-mail: wshou{at}iupui.edu.

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