Androgen Signaling

Androgens mediate a wide range of developmental and physiological responses and are especially important in male sexual differentiation, pubertal sexual maturation, the maintenance of spermatogenesis and male gonadotropin regulation. The unbound androgen receptor (AR) forms a complex with HSPs. The binding of androgens to AR induces dissociation of the AR from the HSPs, subsequent receptor dimerization and translocation into the nucleus.Once in the nucleus, AR binds to its cognate response element and recruits coregulators to promote the expression of target genes. Coactivators such as androgen receptor coactivator, 70-kD (ARA70) and ARA55 stabilize the process of ligand binding to AR. AR interacts with DNA by targeting specific nucleotide palindromic sequences termed androgen response element (ARE). The prototypic coactivators of this type that possess acetyltransferase activity include CBP, the closely related p300,p/CAF and SRC. Transcriptional activation by AR ultimately requires the recruitment of RNA Pol II to the promoter of target genes. RNA Pol II recruitment is mediated through the assembly of general transcription factors to form the preinitiation complex( e.g.TBP, TFIID, and TAFII). Other key transfactors involved are TFIIB and TFIIF. AR can also interact with a number of other transcription factors including Activator Protein-1, SMAD3, NF-κB, Sex-determining Region-Y (SRY), and the Ets family of transcription factors. Transcriptional corepression of androgen-bound AR can be attributed to three corepressors: cyclin-D1, calreticulin and HBO1. Cyclin-D1 inhibits AR transactivation through a mechanism independent of its function in cell cycle regulation.Androgens can activate cAMP and PKA through the SHBG/SHBGR complex. Androgens also stimulate an elevation in intracellular Ca2+ through a GPCR by activating an influx through non-voltage gated Ca2+ channels. The elevation of intracellular calcium activates signal transduction cascades, including PKA, PKC and MAPKs, that can modulate the activity of the ARs and other transcription factors. One of the targets of c-Src is the adapter protein SHC, an upstream regulator of the MAPK pathway. AR phosphorylation by ERK2 is associated with enhanced AR transcriptional activity and an increased ability to recruit the coactivator ARA70.The appropriate regulation of androgen activity is necessary for a range of developmental and physiological processes, particularly male sexual development and maturation. Deregulation of androgen activity is implicated in the formation and progression of prostatic adenocarcinoma.