Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex

Abstract

Androgens, acting through the androgen receptor (AR), are responsible for the development of the male phenotype during embryogenesis, the achievement of sexual maturation at puberty, and the maintenance of male reproductive function and behavior in adulthood. In addition, androgens affect a wide variety of nonreproductive tissues. Moreover, aberrant androgen action plays a critical role in multiple pathologies, including prostate cancer and androgen insensitivity syndromes. The formation of a productive AR transcriptional complex requires the functional and structural interaction of the AR with its coregulators. In the last decade, an overwhelming and ever increasing number of proteins have been proposed to possess AR coactivating or corepressing characteristics. Intriguingly, a vast diversity of functions has been ascribed to these proteins, indicating that a multitude of cellular functions and signals converge on the AR to regulate its function. The current review aims to provide an overview of the AR coregulator proteins identified to date and to propose a classification of these AR coregulator proteins according to the function(s) ascribed to them. Taken together, this approach will increase our understanding of the cellular pathways that converge on the AR to ensure an appropriate transcriptional response to androgens.

Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

“…Data in a-d and f are representative of three independent experiments and is shown as mean ± s.d., *Po0.05. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms2912 ARTICLE Discussion AR requires interactions with its coregulator proteins to actively engage in transcriptional activity 31,32 . Given that many coregulators interact with the AR through motifs containing the consensus LXXLL motif 24 , where L is Leucine and X is any amino acid, we rationally designed peptidomimetics that imitate the LXXLL motif with the aim of disrupting necessary AR-mediated PPIs and thereby inhibit AR signalling and the survival of prostate cancer cells.…”

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].…”

Expression, regulation and function of the ISGylation system in prostate cancer

“…AR activity is modulated by different signal-transduction pathways (Reddy et al, 2006), by cyclins (Olshavsky et al, 2008), by interaction with numerous co-activators and repressors (Heemers and Tindall, 2007) and by diverse posttranslational modifications, including the covalent conjugation of the small ubiquitin-like protein, SUMO-1 (Callewaert et al, 2004). In addition, mutations preferentially occurring in the ligand-binding domain of AR in advanced PCa modify ligand specificity, thereby decreasing the dependence on androgens for the stimulation of proliferation (Taplin and Balk, 2004).…”