S3   LESSONS TO BE LEARNED FROM THE ANDROGEN RECEPTOR

Brinkmann A. O. Department of Endocrinology & Reproduction, Erasmus University Rotterdam, Rotterdam, The Netherlands.

Androgens play a crucial role in several stages of male development. They act via an interaction with the androgen receptor, resulting in regulation of target gene expression. The androgen receptor is a phosphoprotein and modulation of the phosphorylation status of the receptor influences ligand binding and consequently receptor activity. Androgen binding is accompanied by additional receptor phosphorylation. The liganded androgen receptor subsequently interacts with specific androgen response elements in the regulatory regions of target genes, resulting in modulation of gene expression. 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. Two AF functions are ligand dependent (AF1 and AF2),  AF5 functions in a  ligand independent way. Androgen binding results in at least two consecutive conformational changes of the ligand-binding domain.  Anti-androgens induce different conformations of the ligand-binding domain which do not or only partially result in stimulation of transactivation. Recent evidence supports a ligand dependent functional interaction between the ligand-binding domain and the NH₂-terminal transactivating domain of the androgen receptor. Two regions in the NH₂-terminal domain are involved in this interaction, whereas in the ligand binding domain the AF-2 AD core region is involved. At least three pathological situations are associated with abnormal androgen receptor structure and function: (1) androgen insensitivity syndrome (AIS), (2) spinal and bulbar muscular atrophy (SBMA, or Kennedy’s disease) and (3) prostate cancer.