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

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

doi:10.1210/me.2006-0024

Cited by 110 publications

(121 citation statements)

References 51 publications

(54 reference statements)

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“…Thus, the principal role of Fkbp52 must be to control either the DNA recognition or transactivation functions of AR, perhaps by controlling recruitment of co-activators. Interestingly, we obtained similar results for the PR of Fkbp52-deficient females: loss of transactivity but normal hormone-binding function (35). Although Cyp40 or PP5 may account for the normal hormone-binding and translocation activities of these receptors, it is clear that Fkbp52 exerts an unexpected function on both AR and PR that, for the moment, leaves only room for speculation.…”

Section: Discussionsupporting

confidence: 67%

“…To address this question, we have generated both Fkbp52-deficient and Fkbp51-deficient mice. In a prior report (35), we showed that the Fkbp52-deficient female is sterile due to a selective attenuation of some PR-regulated physiologies, in particular the uterine receptivity to implantation. In the current work, we show a similar selectivity of Fkbp52 action in the male.…”

Section: Discussionmentioning

confidence: 72%

“…Instead, the primary phenotype of Fkbp52 ablation was infertility in both male and female mice. Female Fkbp52-deficient mice were sterile due to a selective loss of activity by the PR-A isoform in the uterus, leading to a complete failure of implantation (35). Here, we report that Fkbp52 is critical to male fertility by controlling AR-mediated signaling and physiology.…”

Section: Androgen Receptor (Ar)mentioning

confidence: 82%

“…Fkbp52-deficient females were sterile due to implantation failure. Detailed analysis of Fkbp52-deficient females and the role of Fkbp52 in regulating progesterone receptor function at the uterus was reported elsewhere (35).…”

Section: Resultsmentioning

confidence: 99%

“…Mice-The generation of Fkbp52-deficient mice was described in a previous report (35). To generate Fkbp51-deficient mice, a promoter-trapped ES cell line RRC236 containing an insertional mutation in the mouse Fkbp51 gene was identified and obtained from BayGenomics (36).…”

Section: Generation Of Fkbp52-deficient Mice and Fkbp51-deficientmentioning

confidence: 99%

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Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Yong

Yang

Periyasamy

et al. 2007

Journal of Biological Chemistry

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Androgen receptor (AR)3 is a hormone-induced transcription factor that controls male sexual development and other important physiologies. Similar to other members of the nuclear receptor family (1, 2), AR has three major functional domains: an N-terminal transactivation domain, a DNA-binding domain, and a C-terminal ligand-binding domain (3-5). Mutations found in each of these domains lead to a series of AR functional defects associated with androgen insensitivity syndrome (AIS) or partial AIS in humans (6, 7). The majority of AIS and partial AIS patients have developmental defects in the male reproductive system. Loss-of-function AR mutations in mice recapitulate many of the reproductive defects found in AIS patients. For example, the AR-deficient (androgen receptor knock-out; ARKO) mouse (8) and the tfm (testicular feminization mutant) mouse (9) both develop severe defects of testicular development and an overall lack of male sexual differentiation, including hypospadias and penile agenesis. The tfm male mouse demonstrates many female secondary structures, including vagina and teats (10).Molecular regulation of AR function can be achieved at several levels, such as spatial-temporal expression of the receptor, modulation of ligand binding, cytoplasm to nucleus translocation, and DNA binding and transcriptional activities (11,12). Prior to hormone binding, steroid receptors form large protein complexes containing the molecular chaperone heat shock protein 90 (Hsp90) as well as various co-chaperone tetratricopeptide repeat (TPR) proteins (13-15). These co-chaperones include Fkbp52 and Fkbp51 (FK506-binding protein 52 and 51, respectively), Cyp40 (cyclophilin 40), and PP5 (protein phosphatase 5). Fkbp52 and Fkbp51 are ubiquitously expressed proteins with peptidyl prolyl cis/trans-isomerase activity that is inhibited by the binding of . Each TPR protein enters into steroid receptor complexes through a direct and competitive binding at the C terminus of Hsp90 via its essential TPR domain (19 -21). Although Fkbp52 and Fkbp51 share a similar domain structure, as well as 60% sequence identity and 75% similarity, they do differ in that Fkbp51 is missing a C-terminal calmodulin-binding domain.To date, most studies on TPR control of the steroid receptor (SR) action have been done using conventional molecular and cellular approaches and using the glucocorticoid (GR) and progesterone (PR) receptors as models. It has been shown that Fkbp52 is localized to both cytoplasm and nucleus but that the cytoplasmic fraction co-localizes with microtubules in a complex containing dynein (22, 23). For these reasons, it was pro-

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 72%

Section: Androgen Receptor (Ar)mentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Generation Of Fkbp52-deficient Mice and Fkbp51-deficientmentioning

confidence: 99%

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Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Yong

Yang

Periyasamy

et al. 2007

Journal of Biological Chemistry

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173

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Models of Endometriosis: Animal Models II – Non‐Human Primates

Fazleabas

2011

Endometriosis

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Fluorescent Probes to Characterise FK506‐Binding Proteins

et al. 2009

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Talented all-rounders: Fluorescence polarisation assays were developed for members of the FK506-binding protein family by using fluorescent rapamycin analogues (demonstrated in the figure). These tracers retain medium to high affinity to all tested proteins (FKBP12, -12.6, -13, -25, -51, -52). They can be used for active-site titrations, competition assays with unlabelled ligands and enable a robust, miniaturized assay adequate for high-throughput screening.FK506-binding proteins (FKBPs) convey the immunosuppressive action of FK506 and rapamycin and mediate the neuroprotective properties of these compounds, and participate in the regulation of calcium channels. In addition, the larger homologues FKBP51 and FKBP52 act as cochaperones for Hsp90 and regulate the transactivational activity of steroid hormone receptors. To further characterize these FKBPs, we have synthesized fluorescein-coupled rapamycin analogues. In fluorescence polarization assays one of these compounds retained high affinity to all tested proteins (K(d): 0.1-20 nM) and could be used for active-site titrations. To adapt the fluorescence polarization assay for high-throughput purposes, a simplified rapamycin derivative was synthesized and labelled with fluorescein. This probe showed moderate affinity for the FK1 domains of FKBP51 (177 nM) and FKBP52 (469 nM) and allowed a highly robust, optimized, miniaturized assay (Z'>0.7) sufficient for high-throughput screening of large compound libraries.

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

Cited by 110 publications

References 51 publications

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Models of Endometriosis: Animal Models II – Non‐Human Primates

Fluorescent Probes to Characterise FK506‐Binding Proteins

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