Lessons to be learned from the androgen receptor.

Androgen action is mediated by the androgen receptor, a ligand dependent transcription factor, belonging to the superfamily of nuclear receptors. The two most important androgens are testosterone and 5a-dihydrotestosterone and their tissue specific actions are mediated by the same androgen receptor protein. Binding of androgens by the androgen receptor results in two consecutive conformational changes, which are different from those induced by anti-androgens. The androgen receptor can use different transactivation domains (AF1 and AF5, respectively, in the NH2-terminal domain and AF2-AD in the COOH-terminal domain) depending on the "form" of the receptor protein. The AF2 function is strongly dependent on the presence of nuclear receptor coactivators. Two AF functions are ligand dependent (AF-1 and AF2), whereas AF5 operates in a ligand independent way. The ligand dependency of AF-1 in the full length androgen receptor and the switch to AF5 in the COOH-terminal truncated androgen receptor strongly suggests a functional inhibitory action of the ligand-binding domain on AF-1 in the absence of ligand and on AF5 in the presence of ligand. In vivo experiments favour a ligand dependent functional interaction between the AF-2 AD core region in the ligand-binding domain with the NH2-terminal domain. This interaction might be either direct or indirect, requiring additional factors, and results in androgen receptor driven transcription activation. The androgen receptor protein can undergo two post-translational modifications during receptor activation. Firstly, upon synthesis the protein is rapidly phosphorylated to acquire hormone binding capacities and secondly, upon hormone binding an additional phosphorylation occurs during transformation to the DNA-binding transcription activation form.