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

Zuocheng Yang,Zhuang Chen,Weidong Yong,Sumudra Periyasamy,Weihong Zhao,Weinian Shou,Edwin R SáNchez,Arun Srivastava,Irene M Wolf,Hanying Chen,Jianming Xu,Shu Shi

doi:10.1210/me.2006-0024

Abstract

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.

Highlights

FK506-binding protein 52 (FKBP52) neither disrupted the progesterone receptors (PR)-A/heat shock protein 90 interaction, nor impaired uterine progesterone receptor A isoform (PR-A) hormone-binding function, demonstrating the essential role of FKBP52 in PR-A action to be downstream of the hormone-binding event
Its structure contains a C-terminal site for peptidyl prolyl cis/trans isomerase (PPIase) activity, as well as three centrally located tetratricopeptide repeat (TPR) domains—highly degenerate 34-amino-acid sequences that mediate proteinprotein interactions [11]—that are the site of interaction with Hsp90 [12,13,14]
The complexity of steroid receptor heterocomplexes based on TPR protein content has become apparent

Summary

Introduction

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. 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 provide the basis for selective targeting of steroidregulated physiology through tetratricopeptide repeat proteins. Because the Hsp dimer of receptor complexes generates only one TPR-acceptor site [6, 7], at least four distinct heterocomplexes based on TPR protein content are possible for each steroid receptor. Such heterogeneity implies differential function, almost nothing is known of how TPR proteins influence target cell responses to steroids.

Methods

Results

Conclusion