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Physiological Role for the Cochaperone FKBP52 in Androgen Receptor Signaling

Department of Biochemistry and Molecular Biology (J.C.-F., V.P., M.B.C., D.L.R., D.F.S.), Mayo Clinic College of Medicine, Scottsdale, Arizona 85259; and Department of Cell Biology (C.S.-Q.), Georgetown University Medical Center, Washington, D.C. 20057

Address all correspondence and requests for reprints to: David F. Smith, Department of Biochemistry and Molecular Biology, Johnson Research Building, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. E-mail: smith.david26{at}mayo.edu.

Molecular chaperones mediate multiple aspects of steroid receptor function, but the physiological importance of most receptor-associated cochaperones has not been determined. To help fill this gap, we targeted for disruption the mouse gene for the 52-kDa FK506 binding protein, FKBP52, a 90-kDa heat shock protein (Hsp90)-binding immunophilin found in steroid receptor complexes. A mouse line lacking FKBP52 (52KO) was generated and characterized. Male 52KO mice have several defects in reproductive tissues consistent with androgen insensitivity; among these defects are ambiguous external genitalia and dysgenic prostate. FKBP52 and androgen receptor (AR) are coexpressed in prostate epithelial cells of wild-type mice. However, FKBP52 and AR are similarly coexpressed in testis even though testis morphology and spermatogenesis in 52KO males are usually normal. Molecular studies confirm that FKBP52 is a component of AR complexes, and cellular studies in yeast and human cell models demonstrate that FKBP52 can enhance AR-meditated transactivation. AR enhancement requires FKBP52 peptidylprolyl isomerase activity as well as Hsp90-binding ability, and enhancement probably relates to an affect of FKBP52 on AR-folding pathways. In the presence of FKBP52, but not other cochaperones, the function of a minimally active AR point mutant can be dramatically restored. We conclude that FKBP52 is an AR folding factor that has critically important physiological roles in some male reproductive tissues.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone

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