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Submitted on February 2, 2005
Accepted on April 7, 2005
Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, AZ 85259; Department of Cell Biology, Georgetown University Medical center, Washington, DC 20057
* To whom correspondence should be addressed. E-mail: smith.david26{at}mayo.edu.
Molecular chaperones mediate multiple aspects of steroid receptor function, but the physiological importance of most receptor-associated co-chaperones has not been determined. To help fill this gap, we targeted for disruption the mouse gene for FKBP52, an 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 co-expressed in prostate epithelial cells of wildtype mice. However, FKBP52 and AR are similarly co-expressed 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 co-chaperones, 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.
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