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

Abstract

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-

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…Alcohol-naive adult male and female Fkbp5 knockout (KO) and litter mate wild-type (WT) mice were used. These mice were generated through mating of heterozygous Fkbp5 mice as described in the previous report (Yong et al, 2007). KO mice used for this experiment have been backcrossed with C57BL/6J for four generations.…”

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

“…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). FKBP proteins are validated targets of immunosuppressive drugs.…”

Fkbp52 Regulates Androgen Receptor Transactivation Activity and Male Urethra Morphogenesis

“…Fkbp52-deficient Mice-Fkbp52-deficient mice were generated as described previously (9). They were maintained in a C57BL/6J/129SvEv mixed background.…”

“…Fkbp52 and Fkbp51 are the best known of several tetratricopeptide repeat proteins that co-chaperone steroid receptors, including AR, progesterone receptor, and glucocorticoid receptor (6 -8). Prior work has shown that hypospadias is one of the major physiological defects found in Fkbp52-deficient male mice, but not in Fkbp51-deficient males (9,10). Initial characterization also demonstrated reduced AR-mediated activity when heterologous reporter constructs were transfected into Fkbp52-deficient MEF cells (9).…”

“…Prior work has shown that hypospadias is one of the major physiological defects found in Fkbp52-deficient male mice, but not in Fkbp51-deficient males (9,10). Initial characterization also demonstrated reduced AR-mediated activity when heterologous reporter constructs were transfected into Fkbp52-deficient MEF cells (9). However, the ability of Fkbp52 to regulate endogenous AR-induced genes, the mechanism for this control, and the precise morphogenic events of male urethral development controlled by Fkbp52 are still unknown.…”