Androgen Receptor: Structural Domains and Functional Dynamics after Ligand‐Receptor Interaction

Abstract

Androgens are C‐19 steroids secreted primarily from the testes and adrenals that play a critical role in reproduction. Reproductive functions of androgens are mediated through coordination of diverse physiological processes ranging from brain functions to specific cell proliferation and apoptosis. At the molecular level, most of these regulatory influences are exerted by altered expression of appropriate genes by the androgen receptor (AR), a member of the nuclear receptor (NR) superfamily. The unliganded AR is a cytoplasmic protein and, upon ligand binding, it translocates into the nucleus. Thereafter, in conjunction with other transcription factors and coactivators, the AR influences transcription of target genes through a multistep process that includes its clustering in a subnuclear compartment. Here, we describe the genomic organization of the AR, the role of individual structural domains in specific AR function, and the influence of agonistic/antagonistic ligands in the intracellular movement of the receptor. We also show that the AR is capable of undergoing multiple rounds of nucleocytoplasmic recycling after ligand binding and dissociation. Xenobiotic ligands, considered as selective androgen receptor modulators (SARMs), can modulate AR activity by inhibiting either its nuclear translocation or its subnuclear clustering and subsequent transactivation function.

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…3G and Supplementary Fig. S7), these AR foci have previously been reported and correlate with AR-mediated activity (36)(37)(38).…”

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

“…2 Hormone-receptor complexes bind to certain hormone responsive DNA sequences proximal to target genes and regulate their expression. [1][2][3] It is well demonstrated that castration in rodent models or androgen ablation in cell culture system causes a rapid apoptotic response in the prostate-derived epithelial cells. 4,5 Based on these phenomena, androgen ablation therapy has been used in clinical management of prostate cancer patients.…”

Testosterone inhibits matrix metalloproteinase-1 production in human endometrial stromal cells in vitro

“…Human uterine endometrium is a typical steroid hormone-responsive organ under the influence of steroid hormones, especially estrogen and progesterone, but little is known about the action of androgens, which are the other type of steroid hormone. The biological actions of androgens are mediated by androgen receptor (AR), a ligand-dependent transcription factor, which belongs to the nuclear receptor superfamily (Roy et al 2001). Immunohistochemical localization of AR in the human endometrium has been reported (Mertens et al 2001, Slayden et al 2001, Apparao et al 2002.…”