The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions

Abstract

The biological activity of testosterone and dihydrotestosterone is thought to occur predominantly through binding to the androgen receptor (AR), a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor. However, androgens have also been reported to induce the rapid activation of kinase-signaling cascades and modulate intracellular calcium levels. These effects are considered to be nongenomic because they occur in cell types that lack a functional AR, in the presence of inhibitors of transcription and translation, or are observed to occur too rapidly to involve changes in gene transcription. Such nongenomic effects of androgens may occur through AR functioning in the cytoplasm to induce the MAPK signal cascade. In addition, androgens may function through the sex hormone binding globulin receptor and possibly a distinct G protein-coupled receptor to activate second messenger signaling mechanisms. The physiological effect of nongenomic androgen action has yet to be determined. However, it may ultimately contribute to regulation of transcription factor activity, including mediation of the transcriptional activity of AR.

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…Most extensively, this activity (tentatively named R SHBG ) has been studied in the breast cancer cell line MCF7. In this cell type, SHBG has been implicated in cAMP-dependent signaling of bound-estradiol (Heinlein and Chang, 2002;Kahn et al, 2008;Nakhla et al, 1999;Rosner et al, 1999). Furthermore, the carrier has been shown to antagonize estradiol-induced proliferation of these cells by inhibiting the activation of extracellular regulated kinase (ERK) -1/-2 (Catalano et al, 2005) and by regulating expression of downstream target genes involved in cell growth and Page 7 of 44 A c c e p t e d M a n u s c r i p t 7 apoptosis (Catalano et al, 2007;Fortunati and Catalano, 2006).…”

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

“…After ligand binding, heat-shock proteins dissociate from the receptor, and then the AR translocates to the nucleus [3], where it regulates transcription by binding to specific androgen response elements in promoters of target genes. Together with co-regulatory proteins and general transcription factors, a stable transcription initiation complex is formed [4][5][6]. An important feature of ligand binding is that it induces a conformational change in the AR LBD (ligand-binding domain), providing a surface for interactions with co-regulatory proteins.…”

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

“…In addition, AR mediates nongenomic androgen effects, intracellular calcium flux and kinase activation. 3 In androgen-independent cell lines, AR may cause cell growth in the absence of ligand. 4 Unlawful AR activation can occur without steroids via surface receptors, like HER-2, 5 or by growth factors, like interleukin-6, oncostatin-M or bombesin.…”