Androgen Receptor (AR) Coregulators: An Overview

Abstract

The biological action of androgens is mediated through the androgen receptor (AR). Androgen-bound AR functions as a transcription factor to regulate genes involved in an array of physiological processes, most notably male sexual differentiation and maturation, and the maintenance of spermatogenesis. The transcriptional activity of AR is affected by coregulators that influence a number of functional properties of AR, including ligand selectivity and DNA binding capacity. As the promoter of target genes, coregulators participate in DNA modification, either directly through modification of histones or indirectly by the recruitment of chromatin-modifying complexes, as well as functioning in the recruitment of the basal transcriptional machinery. Aberrant coregulator activity due to mutation or altered expression levels may be a contributing factor in the progression of diseases related to AR activity, such as prostate cancer. AR demonstrates distinct differences in its interaction with coregulators from other steroid receptors due to differences in the functional interaction between AR domains, possibly resulting in alterations in the dynamic interactions between coregulator complexes.

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…Testosterone and 5a-dihydrotestosterone exert their biological effects through binding and transactivating AR (Heinlein and Chang, 2002;Heinlein and Chang, 2004;Rahman et al, 2004;Wang et al, 2005), which involves interaction of AR with various coregulators during prostate development and prostate cancer progression (Heinlein and Chang, 2002;Rahman et al, 2004;Wang et al, 2005).…”

Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53

“…The proper function of AR requires coregulators for its optimal signalling. Several AR coregulators, including the cAMP response element-binding protein-binding protein, steroid receptor coactivator 1, ARA54, ARA67/PAT1, ARA70, hRad9 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been identified [3,[13][14][15][16][17][18]. ARA54 enhances AR transactivation in a ligand-dependent manner [17,19,20].…”

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

“…14 The AR contains a highly variable amino-terminal domain (NTD) essential for receptor stabilization 15,16 that also regulates its transcriptional activity by providing an interaction surface for key prostate-specific co-regulators and the transcriptional machinery. 17 The AR-NTD signature (ANTS) sequence, composed of amino acids 234-247 (229-242 in mice), is the most evolutionarily conserved region of the AR but, interestingly, is not found in related steroid receptors. 13,18 Mutations have been identified proximal to the ANTS sequence in clinical prostate cancers 2 and within or near this sequence in castrate-resistant tumors arising in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model.…”