Mechanisms of androgen receptor activation and function

Androgens play a crucial role in several stages of male development and in the maintenance of the male phenotype. Androgens act in their target cells via an interaction with the androgen receptor, resulting in direct regulati on of gene expression. The androgen receptor is a phosphoprotein and modula tion of the phosphorylation status of the receptor influences ligand-bindin g and consequently transcription activation of androgen responsive genes. A ndrogen binding induces a conformational change in the ligand-binding domai n, accompanied by additional receptor phosphorylation. Subsequently the lig anded androgen receptor interacts with specific androgen response elements in the regulatory regions of androgen target genes, resulting in stimulatio n of gene expression. Anti-androgens induce a different conformational chan ge of the ligand-binding domain, which does not or only partially result in stimulation of transactivation. Interestingly, different anti-androgens ca n induce different inactive conformations of the androgen receptor ligand-b inding domain. Recent evidence strongly supports a ligand dependent functio nal interaction between the ligand-binding domain and the NH2-terminal tran sactivating domain of the androgen receptor. Two regions in the NH2-termina l domain are involved in this interaction, whereas in the ligand-binding do main the AF-2 AD core region is involved. (C) 1999 Elsevier Science Ltd. Al l rights reserved.