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Submitted on January 12, 2006
Accepted on July 21, 2006
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Pediatrics, Third Xiang-Ya Hospital, Central South University, Xiang-Ya School of Medicine, Changsha, P.R. China; Department of Pharmacology, Medical University of Ohio, Toledo, OH43614, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA; The First Affiliated Hospital of Nanjing medical University, Nanjing, Jiangsu 210029, P.R. China; Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
* To whom correspondence should be addressed. E-mail: esanchez{at}meduohio.edu or wshou{at}iupui.edu.
FKBP52 is a tetratricopeptide repeat (TPR) protein that associates with steroid receptors in complexes containing heat shock protein (Hsp90). 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 receptor (PR). Since 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 unable 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 did not disrupt the PR-A/Hsp90 interaction, nor impair uterine PR-A hormone-binding function, demonstrating the essential role of FKBP52 in PR-A action to be down-stream of the hormone-binding event. Transcription studies in +/+ and -/- mouse embryonic fibroblast cells showed a near-complete loss of PR-A activity at MMTV and synthetic PRE 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 non-essential 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 TPR proteins.
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