Protein-protein Interactions of the Androgen Receptor in Living Cells

Abstract

Natural androgens, testosterone (T) and its derivative dihydrotestosterone (DHT) play a crucial role in the development and maintenance of the male phenotype. Androgens are steroids that exert their function via the androgen receptor (AR), a ligand dependent transcription factor. The human AR gene, is located on the X chromosome, and contains 8 exons, coding for a 110 kDa, 919 amino acids protein (Brinkmann et al., 1989; Hughes and Deeb, 2006). In the classical model of AR action, the unliganded AR is located in the cytoplasm in complex with chaperone proteins (Pratt and Toft, 1997; Prescott and Coetzee, 2006). Upon androgen binding the chaperone complex is modifi ed and the AR translocates to the nucleus (Georget et al., 1997; Tyagi et al., 2000; Black and Paschal, 2004). In the nucleus, the AR binds to specifi c sequences in promoters and enhancers of target genes, interacts with specifi c coregulators and enhances the recruitment of the general transcription machinery, leading to transcription initiation (Fig. 1) (Glass and Rosenfeld, 2000; Claessens et al., 2001; Cosma, 2002; Orphanides and Reinberg, 2002; Heemers and Tindall, 2007). Recently, many reviews on AR function have been published (e.g. Dehm and Tindall, 2007; Heemers and Tindall, 2007; Trapman and Dubbink, 2007; Centenera et al., 2008; Claessens et al., 2008). The focus of this thesis is on molecular mechanisms underlying AR function in living cells.