The FK506-Binding Immunophilin FKBP51 Is Transcriptionally Regulated by Progestin and Attenuates Progestin Responsiveness

Abstract

FKBP51 and FKBP52 are large molecular weight FK506-binding immunophilins that have diverse biochemical functions. Best studied is the role that they play as components of steroid hormone receptors. Differential display and gene array screens have identified FKBP51 as a progestin-inducible gene. Here we demonstrate progestin enhancement of FKBP51 mRNA and protein in T-47D cells. FKBP51 mRNA and protein levels were increased 3-fold by 20 nM R5020. Induction of FKBP51 mRNA was unaffected by 1 micro g/ml cycloheximide but was blocked by the progestin receptor (PR) antagonist RU486 (1 micro M). Reporter plasmids containing 3.4 kb and 427 bp of 5'-flanking sequences of the human FKBP51 protein gene (FKBP5) exhibited regulation by progestin in T-47D cells. A construct containing 19 bp of upstream sequence demonstrated diminished basal activity and no stimulation by R5020. To test whether elevated FKBP51 affects progestin responsiveness, HepG2 cells were transfected with human FKBP51, PR, and mouse mammary tumor virus-luciferase plasmids, and treated with R5020 (0.03-10 nM). Expression of FKBP51 increased the EC(50) for PR transactivation by 3.2-fold. Expression of FKBP51 from squirrel monkey, a New World primate with naturally occurring progestin resistance, increased the EC(50) more dramatically (11.7-fold vs. control). Expression of FKBP51 bearing a double-point mutation in the tetratricopeptide repeat domain had no effect on PR transactivation. These results suggest that increased expression of FKBP51 by progestin may attenuate progestin responsiveness in hormone-conditioned cells. Furthermore, overexpression of FKBP51 in the squirrel monkey may be a contributing cause of progesterone resistance in this species.

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

“…In the course of analyzing TPR expression levels in the tissues of wild type and Fkbp52-deficient mice, we found a dramatic down-regulation of Fkbp51 in Fkbp52-deficient penile tissue but not in the Fkbp52-deficient testis. Because Fkbp51 is a known target gene of AR action (29,32,33), this result was further evidence of compromised AR activity in the penis but not the testis. Moreover, since there is at least one report that Fkbp51 overexpression in prostate cells enhances AR activity (32), the interesting possibility was raised that a genetic interplay may exist between Fkbp52 and Fkbp51, perhaps for the purpose of regulating the tissue-selective functions of AR.…”

“…Indeed, various groups have shown that Fkbp52 contributes to both the dynein interaction and hormone-induced translocation of GR (25)(26)(27). Meanwhile, a second line of inquiry has provided evidence for reciprocal control of GR and PR hormone binding function by Fkbp52 and Fkbp51, with Fkbp52 causing potentiation and Fkbp51 causing attenuation of this activity (15,28,29). These observations suggest a model in which differential incorporation of TPR proteins into SR com- and d) indicate the underdeveloped foreskin and ectopic urethral opening at the ventral aspect compared with normal morphology in controls (a and c).…”

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

“…We extended this analysis to the regulation in T47D cells of progesterone target genes encoding IGFBP1, mucin 1 (MUC1) and FK506-binding protein 5 (FKBP51) (4,38,39) (Fig. 7).…”

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

“…Remarkably, recruitment of FKBP51 as a cochaperone to Hsp90 protein complexes modulates the activity of other nuclear receptors, besides GR. 42,43 It is thus likely that SUMO conjugation to FKBP51 may impact on their activity as well. Further studies will be needed to address the overall significance of this mechanism on other nuclear receptors and in different contexts.…”