Fig. 2.

Classical mechanisms of androgen signaling in a target cell. In circulation, testosterone is bound to the serum sex hormone-binding globulin (SHBG). Testosterone dissociates from its binding carrier protein and diffuses freely through the cell membrane. Once in the cytoplasm, testosterone can be converted to its active metabolite 5α-dihydrotestosterone (DHT). Testosterone or DHT can directly bind to the androgen receptor (AR) leading to the dissociation of heat shock proteins (hsp) from the inactive receptor. The ligand-bound receptor then exerts its effects by rapid nongenomic effects by modulating the activity of the Src/Raf-1/Erk-2 pathway or the phosphoinositide 3-kinase (PI3K)/AKT pathway, or by genomic mechanisms involving the activated AR translocation into the nucleus. In the nucleus the androgen receptor binds as homodimer to specific DNA elements present as enhancers in upstream promoter sequences of androgen target genes. Upon AR binding, coactivators are recruited and the basal transcription machinery (BTM) (e.g. RNA-polymerase II [RNA-Pol II], TATA box binding protein [TBP], TBP associating factors [TAF's], general transcription factors [GTF's]) is activated. The interactions between AR, coactivators and the BTM results in gene transcription.