Hypospadias is a common birth defect. Although its etiology is unknown, it is generally considered to arise from androgen insensitivity. In 1997, the Center for Disease Control and Prevention (CDC) released reports documenting an increase of almost 100% in hypospadias cases in the US from 1968 to 1993. It was suggested that environmental contamination by endocrine disrupting agents might have contributed to this outbreak. In spite of its high prevalence, mutations in androgen receptor (AR) or 5D-reductase have been found in less than 2% of the hypospadias patient population, suggesting that multiple targets in the pathways of androgen signaling or metabolism contribute to hypospadias. Surgical repair is the only treatment for hypospadias. Lack of an animal model for hypospadias has limited our efforts to identify the pathogenesis of the disease, as well as development of new therapies. In this application, we will investigate our discovery that the FK506-binding rjrotein, FKBP52, is involved in the etiology of hypospadias. FKBP52 is also known as a steroid receptor associated-tetratricorjeptide repeat domain protein (SRA-TPR) based on its ability to enter into heterocomplexes with steroid receptors via a direct interaction with heat shock protein 90 (Hsp90). FKBP52 is one of several SRA-TPRs and is found in the AR complex, as well as in progesterone receptor (PR) and glucocorticoid receptor (GR) complexes. In the GR system, FKBP52 is known to increase the binding affinity for hormone, while FKBP51 (a closely-related SRA-TPR) serves to attenuate (but not abolish) this function. In an effort to study the role of FKBP52 in vivo, we generated FKBP52-deficient mice. Strikingly, FKBP52-deficientmales give rise to severe hypospadias with 100% penetrance. Our initial morphological and histological characterization at both embryonic and adult stages revealed an essential role of FKBP52 in androgen-mediated male genital development.Accordingly,this proposal will test the hypothesis that FKBP52 is a key regulator of ligand-induced androgen receptor action and is critical to male urethral and genital development. We will test this hypothesis in the following ways: 1)we will determine the developmental mechanism of ventral urethral epithelium closure and male genital development;2) we will determine the role of FKBP52 in androgen receptor signaling at both the cellular and molecular level;3) we will study the contribution of FKBP51 to AR function and the development of hypospadias using mouse genetic tools.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Hoshizaki, Deborah K
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Stechschulte, Lance A; Hinds Jr, Terry D; Khuder, Saja S et al. (2014) FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GR? and PPAR?. Mol Endocrinol 28:1265-75
Stechschulte, Lance A; Hinds Jr, Terry D; Ghanem, Simona S et al. (2014) FKBP51 reciprocally regulates GR? and PPAR? activation via the Akt-p38 pathway. Mol Endocrinol 28:1254-64
Hinds Jr, Terry D; Stechschulte, Lance A; Cash, Harrison A et al. (2011) Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-? (PPAR?). J Biol Chem 286:42911-22
Periyasamy, S; Hinds Jr, T; Shemshedini, L et al. (2010) FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 29:1691-701
Chen, Hanying; Yong, Weidong; Hinds Jr, Terry D et al. (2010) Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis. J Biol Chem 285:27776-84
Warrier, Manya; Hinds Jr, Terry D; Ledford, Kelly J et al. (2010) Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice. Endocrinology 151:3225-36
Wolf, Irene M; Periyasamy, Sumudra; Hinds Jr, Terry et al. (2009) Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity. J Steroid Biochem Mol Biol 113:36-45
Banerjee, Ananya; Periyasamy, Sumudra; Wolf, Irene M et al. (2008) Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins. Biochemistry 47:10471-80
Periyasamy, Sumudra; Warrier, Manya; Tillekeratne, Manoranjani P M et al. (2007) The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms. Endocrinology 148:4716-26
Yong, Weidong; Bao, Shideng; Chen, Hanying et al. (2007) Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest. J Biol Chem 282:14690-4

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