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

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99 Scopus citations

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 (US)
Pages (from-to)2682-2694
Number of pages13
JournalMolecular Endocrinology
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Yang, Z., Wolf, I. M., Chen, H., Periyasamy, S., Chen, Z., Yong, W., Shi, S., Zhao, W., Xu, J., Srivastava, A., Sánchez, E. R., & Shou, W. (2006). FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. Molecular Endocrinology, 20(11), 2682-2694. https://doi.org/10.1210/me.2006-0024