Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation

Abstract

Embryo implantation in the uterus is a critical step in mammalian reproduction, requiring preparation of the uterus receptive to blastocyst implantation. Uterine receptivity, also known as the window of implantation, lasts for a limited period, and it is during this period blastocysts normally implant. Ovarian steroid hormones estrogen and progesterone (P 4) are the primary regulators of this process. The immunophilin FKBP52 serves as a cochaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Here we show a critical role for FKBP52 in mouse implantation. This immunophilin has unique spatiotemporal expression in the uterus during implantation, and females missing the Fkbp52 gene have complete implantation failure due to lack of attainment of uterine receptivity. The overlapping uterine expression of FKBP52 with nuclear progesterone receptor (PR) in wild-type mice together with reduced P 4 binding to PR, attenuated PR transcriptional activity and down-regulation of several P4-regulated genes in uteri of Fkbp52 ؊/؊ mice, establishes this cochaperone as a critical regulator of uterine P4 function. Interestingly, ovulation, another P4-mediated event, remains normal. Collectively, the present investigation provides evidence for an in vivo role for this cochaperone in regulating tissue-specific hormone action and its critical role in uterine receptivity for implantation.mouse ͉ uterus ͉ ovulation ͉ blastocyst ͉ progesterone receptor P rogesterone (P 4 ) is essential for implantation and pregnancy maintenance in all mammalian species studied. In mice, P 4 priming of the uterus is obligatory for estrogen to prepare the uterus to the receptive state conducive to blastocyst implantation. P 4 acting through the nuclear P 4 receptor (PR) modulates uterine physiology and expression of various genes that are required for implantation (1, 2). Numerous defects in mice lacking the Pgr gene that encodes PR include failure in ovulation, mammary gland development, and sexual behavior along with uterine hyperplasia and inflammation, reflecting the critical role of P 4 in female reproduction (3). Appropriate functioning of nuclear steroid hormone receptors depends on interactions with the molecular chaperone machinery to maintain a functional state competent for hormone binding and subsequent transcriptional activation. Functionally mature steroid receptor complexes consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of four cochaperones that contain a tetratricopeptide repeat (TPR) domain. The TPR cochaperones include two members of the FK506 binding family of immunophilins, FKBP52͞FKBP4 and FKBP51͞FKBP5, a member of the cyclosporin-binding immunophilin cyclophilin 40 (CyP40) or the protein phosphatase PP5. FKBP52 and FKBP51 are similar to other FKBP family members in that both contain an active peptidylprolyl cis͞trans isomerase domain that catalyzes conformational changes in protein substrates (4, 5).Roles for Hsp90 and p23 in initia...

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

“…We found that Fkbp52 −/− females on both C57BL6/129 mixed and CD1 backgrounds have implantation failure with normal ovulation (8,9). However, P 4 supplementation rescues implantation and decidualization in CD1, but not in C57BL6/129, Fkbp52 −/− females.…”

“…WT and Fkbp52 −/− MEFs (kindly provided by Marc B. Cox, University of Texas, El Paso, TX) were isolated as described previously (8). The cells were maintained in DMEM supplemented with 10% FBS and penicillin/streptomycin.…”

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

“…The final mature complex in which the receptor is capable of high affinity hormone binding includes heat shock protein 90 (Hsp90), a 23 kDa cochaperone (p23), and one of a class of proteins (termed FKBPs) characterized by their Hsp90-binding tetratricopeptide repeat (TPR) domain. The 52 kDa FK506 binding protein (FKBP52) associates with receptor-Hsp90 complexes by way of a C-terminal TPR domain and is a specific positive regulator of AR, glucocorticoid receptor (GR), and progesterone receptor (PR) signaling (3)(4)(5). FKBP52 is required for normal male sexual differentiation and development in mice as the fkbp52-deficient mice (52KO) display characteristics of partial androgen insensitivity syndrome including dysgenic prostate (4,6).…”

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

“…P 4 signaling inhibits the estrogen signaling pathways in the uterus (Hsueh et al 1975) and this inhibitory relationship involving both hormone pathways orchestrate the regulatory mechanisms required for endometrial receptivity and embryo implantation. Amongst the regulated transcripts in the mid-secretory endometrium from women with mifepristone administration we found several genes involved in the P 4 signaling axis including modulators and effectors with down regulation of NCOA2 (SRC-2, (Mukherjee et al 2006, Jeong et al 2007), IHH (Matsumoto et al 2002, Takamoto et al 2002, ERRFI1 (MIG6, (Kim et al 2010)) PTCH1 (Lee et al 2006) and DKK1 ; and up-regulation of ESR1 (Curtis et al 1999), PRA (Conneely & Lydon 2000), FKBP5 (Tranguch et al 2005), FOXO1A (Kim et al 2005), KLF9 (Simmen et al 2004) and PTGS1 (Wang et al 2004).…”