FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform.
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.
Yang
Zuocheng
Z
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Wolf
Irene M
IM
Chen
Hanying
H
Periyasamy
Sumudra
S
Chen
Zhuang
Z
Yong
Weidong
W
Shi
Shu
S
Zhao
Weihong
W
Xu
Jianming
J
Srivastava
Arun
A
Sánchez
Edwin R
ER
Shou
Weinian
W
D000818:Animals; D002478:Cells, Cultured; D010064:Embryo Implantation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010060:Ovulation / Q000235:genetics; D011374:Progesterone / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000502:physiology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism / Q000502:physiology*; D012098:Reproduction / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014599:Uterus / Q000502:physiology*
D020033:Protein Isoforms; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D011374:Progesterone; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4