Androgen receptor (AR)3 is a hormone-induced transcription factor that controls male sexual development and other important physiologies. Similar to other members of the nuclear receptor family (1, 2), AR has three major functional domains: an N-terminal transactivation domain, a DNA-binding domain, and a C-terminal ligand-binding domain (3-5). Mutations found in each of these domains lead to a series of AR functional defects associated with androgen insensitivity syndrome (AIS) or partial AIS in humans (6, 7). The majority of AIS and partial AIS patients have developmental defects in the male reproductive system. Loss-of-function AR mutations in mice recapitulate many of the reproductive defects found in AIS patients. For example, the AR-deficient (androgen receptor knock-out; ARKO) mouse (8) and the tfm (testicular feminization mutant) mouse (9) both develop severe defects of testicular development and an overall lack of male sexual differentiation, including hypospadias and penile agenesis. The tfm male mouse demonstrates many female secondary structures, including vagina and teats (10).Molecular regulation of AR function can be achieved at several levels, such as spatial-temporal expression of the receptor, modulation of ligand binding, cytoplasm to nucleus translocation, and DNA binding and transcriptional activities (11,12). Prior to hormone binding, steroid receptors form large protein complexes containing the molecular chaperone heat shock protein 90 (Hsp90) as well as various co-chaperone tetratricopeptide repeat (TPR) proteins (13-15). These co-chaperones include Fkbp52 and Fkbp51 (FK506-binding protein 52 and 51, respectively), Cyp40 (cyclophilin 40), and PP5 (protein phosphatase 5). Fkbp52 and Fkbp51 are ubiquitously expressed proteins with peptidyl prolyl cis/trans-isomerase activity that is inhibited by the binding of . Each TPR protein enters into steroid receptor complexes through a direct and competitive binding at the C terminus of Hsp90 via its essential TPR domain (19 -21). Although Fkbp52 and Fkbp51 share a similar domain structure, as well as 60% sequence identity and 75% similarity, they do differ in that Fkbp51 is missing a C-terminal calmodulin-binding domain.To date, most studies on TPR control of the steroid receptor (SR) action have been done using conventional molecular and cellular approaches and using the glucocorticoid (GR) and progesterone (PR) receptors as models. It has been shown that Fkbp52 is localized to both cytoplasm and nucleus but that the cytoplasmic fraction co-localizes with microtubules in a complex containing dynein (22, 23). For these reasons, it was pro-

FK506-binding protein 52 (FKBP52) is a tetratricopeptide repeat protein that associates with steroid receptors in complexes containing heat shock protein 90. To investigate the role of FKBP52 in steroid-regulated physiology, we generated FKBP52-deficient mice. FKBP52 (-/-) females are sterile due to a complete failure of implantation, a process that requires estrogen (ER) and progesterone receptors (PR). Because the uterus expresses two forms of PR, PR-A and PR-B, we investigated all three receptors as potential targets of FKBP52 action. FKBP52 (-/-) uteri showed a normal growth response to estradiol, and unaltered expression of genes controlled by ER and PR-B. In contrast, FKBP52 (-/-) uteri were neither able to express two PR-A-regulated genes, nor undergo decidualization in response to progesterone, suggesting that FKBP52 specifically regulates PR-A at this organ. Analysis of uterine PR heterocomplexes showed preferential association of FKBP52 with PR-A compared with PR-B. Loss of FKBP52 neither disrupted the PR-A/heat shock protein 90 interaction, nor impaired uterine PR-A hormone-binding function, demonstrating the essential role of FKBP52 in PR-A action to be downstream of the hormone-binding event. Transcription studies in +/+ and -/- mouse embryonic fibroblast cells showed a near-complete loss of PR-A activity at mouse mammary tumor virus and synthetic progesterone response element promoters, although partial reductions of ER and PR-B were also observed. Partial disruptions of ovulation and mammary development were also found in FKBP52 (-/-) females. Taken as a whole, our results show FKBP52 to be an essential regulator of PR-A action in the uterus, while being a nonessential but contributory regulator of steroid receptors in the mammary and ovary. These data may now provide the basis for selective targeting of steroid-regulated physiology through tetratricopeptide repeat proteins.

Background:The glucocorticoid (GR) and peroxisome proliferator-activated (PPAR␥) receptors are antagonists of lipid metabolism. Results: Protein phosphatase 5 (PP5) dephosphorylates GR and PPAR␥ to reciprocally control their activities. Conclusion: PP5 is a switch point in nuclear receptor control of lipid metabolism. Significance: PP5 is a potential new drug target in the treatment of obesity.

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