FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2682-2694
Number of pages13
JournalMolecular Endocrinology
Volume20
Issue number11
DOIs
StatePublished - Nov 2006

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Tacrolimus Binding Proteins
Protein Isoforms
Uterus
Progesterone Receptors
Estrogen Receptors
HSP90 Heat-Shock Proteins
Steroid Receptors
progesterone receptor A
Progesterone
Breast
Steroids
Hormones
Mouse mammary tumor virus
Response Elements
Ovulation

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. / Yang, Zuocheng; Wolf, Irene M.; Chen, Hanying; Periyasamy, Sumudra; Chen, Zhuang; Yong, Weidong; Shi, Shu; Zhao, Weihong; Xu, Jianming; Srivastava, Arun; Sánchez, Edwin R.; Shou, Weinian.

In: Molecular Endocrinology, Vol. 20, No. 11, 11.2006, p. 2682-2694.

Research output: Contribution to journalArticle

Yang, Z, Wolf, IM, Chen, H, Periyasamy, S, Chen, Z, Yong, W, Shi, S, Zhao, W, Xu, J, Srivastava, A, Sánchez, ER & Shou, W 2006, 'FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform', Molecular Endocrinology, vol. 20, no. 11, pp. 2682-2694. https://doi.org/10.1210/me.2006-0024
Yang, Zuocheng ; Wolf, Irene M. ; Chen, Hanying ; Periyasamy, Sumudra ; Chen, Zhuang ; Yong, Weidong ; Shi, Shu ; Zhao, Weihong ; Xu, Jianming ; Srivastava, Arun ; Sánchez, Edwin R. ; Shou, Weinian. / FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. In: Molecular Endocrinology. 2006 ; Vol. 20, No. 11. pp. 2682-2694.
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