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FK506-Binding Protein 52 Is Essential to Uterine Reproductive Physiology Controlled by the Progesterone Receptor A Isoform

Herman B Wells Center for Pediatric Research (Z.Y., H.C., Z.C., W.Y., S.S., W.S.), Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pediatrics (Z.Y.), Third Xiang-Ya Hospital, Central South University, Xiang-Ya School of Medicine, Changsha, People’s Republic of China; Department of Pharmacology (I.M.W., S.P., E.R.S.), Medical University of Ohio, Toledo, Ohio 43614; Department of Pediatrics (W.Z., A.S.), University of Florida, Gainesville, Florida 32611; The First Affiliated Hospital of Nanjing medical University (W.Z.), Nanjing, Jiangsu 210029, People’s Republic of China; and Department of Molecular and Cell Biology (J.Z.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Weinian Shou, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202. E-mail: wshou{at}iupui.edu or esanchez{at}meduohio.edu.

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.

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