FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT

Abstract

Defective decidualization of human endometrial stromal cells (ESCs) has recently been highlighted as an underlying cause of implantation failure. FK-506-binding protein 51 (FKBP51) has been shown to participate in the steroid hormone response and the protein kinase B (AKT) regulation process, both of which are important pathways involved in decidualization. The objective of the present study was to investigate the potential effects and mechanisms of FKBP51 in the regulation of ESC decidualization. By performing immunohistochemical staining on an endometrial tissue microarray (TMA) derived from normal females, we found that FKBP51 expression was much higher in the luteal phase than in the follicular phase in ESCs. Primary ESCs were isolated from patients to build an decidualization model through co-culture with medroxyprogesterone acetate (MPA) and 8-bromoadenosine (cAMP). SC79, a specific AKT activator in various physiological and pathological conditions, and shRNA-FKBP51 were used to examine the roles of AKT and FKBP51 in decidualization. The Western blot and RT-PCR results showed that FKBP51, insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL) expression increased in ESCs treated with MPA + cAMP; meanwhile, the level of p-Ser473 AKT (p-S473 AKT) decreased and forkhead box protein O1 (FOXO1A) expression increased. Decidualization was inhibited by the AKT activator SC79 and the transfection of FKBP51-shRNA by affecting protein synthesis, cell morphology, cell growth and cell cycle. Furthermore, this inhibition was rescued by FKBP51-cDNA transfection. The results supported that FKBP51 promotes decidualization by reducing the Ser473 phosphorylation levels in AKT.

Microgravity inhibits decidualization via decreasing Akt activity and FOXO3a expression in human endometrial stromal cells

“…These results suggested that another regulation pathway may induce the decrease in Akt phosphorylation under SM conditions. Since the regulation of Akt activity by phosphatases, such as PP2A in endometrial cancer 22 and FKBP51 in the decidualization of human eSCs 23 has been reported in human eSCs, SM may activate Akt-specific phosphatases, which resulted in a decrease in Akt phosphorylation. Whether PP2A or FKBP51 is involved in SM-induced decrease in Akt activity warrants further investigation.…”

FKBP51 promotes invasion and migration by increasing the autophagic degradation of TIMP3 in clear cell renal cell carcinoma

“…IHC was carried out as previously described [ 26 ]. The primary antibodies were rabbit anti-FKBP51 (Abcam, ab126715, diluted: 1:200), rabbit anti-TIMP3 (Abcam, ab39184, diluted: 1:300), rabbit anti-MMP7 (Abcam, ab205525, diluted: 1:200), and rabbit anti-MMP9 (Abcam, ab39184, diluted: 1:200).…”

“…Researchers also found that FKBP51 acts as a cofactor of the IκB-kinase (IKK) complex, induces the activation of the NF-κB pathway and promotes the progression of prostate cancers, melanoma, and glioblastoma [ 22 – 25 ]. Similarly, our team has previously reported that FKBP51 promotes endometrial cancer and thyroid cancer and plays a role in the remodeling process of endometrial decidualization [ 26 , 27 ]. These findings suggest that FKBP51 may play an important role in the regulation of ECM functions and influence the invasion and migration of tumor cells.…”

CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis

“…ESCs were cultured in phenol-red-free DMEM/F-12 maintenance medium (Gibco, Waltham, MA, USA) containing 10% charcoalstripped fetal bovine serum (CS-FBS). 56,57 The ESCs were then treated with 0.5 mM db-cAMP (cAMP; Sigma, St. Louis, MO, USA) and 1 mM medroxyprogesterone acetate (MPA; Sigma, St. Louis, MO, USA) for 2-6 days to induce in vitro decidualization in DMEM/F-12 differentiation medium containing 2% CS-FBS, 57,58 and the medium was changed every 48 h. Cells and supernatants were collected at different times (days 0, 2, 4, and 6) to measure the mRNA and protein levels of the decidualization markers (PRL and IGFBP1). Different doses of 17AAG (Selleck, Houston, TX, USA), the specific inhibitor of HSP90, and MK-2206 (Selleck, Houston, TX, USA), the selective inhibitor of AKT1/2/3, were added to the above-mentioned differentiation medium to investigate the effects of HSP90 and the AKT pathway on cell functions.…”