Physiological role for the cochaperone FKBP52 in androgen receptor signaling.
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-mediated 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.
Cheung-Flynn
Joyce
J
Department of Biochemistry and Molecular Biology, Johnson Research Building, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA.
Prapapanich
Viravan
V
Cox
Marc B
MB
Riggs
Daniel L
DL
Suarez-Quian
Carlos
C
Smith
David F
DF
D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D005822:Genetic Vectors; D005838:Genotype; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D008958:Models, Molecular; D018832:Molecular Chaperones; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011392:Proline / Q000737:chemistry; D011467:Prostate / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000502:physiology*; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution; D015533:Transcriptional Activation
D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011944:Receptors, Androgen; D011392:Proline; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4