Selective DNA recognition by the androgen receptor as a mechanism for hormone-specific regulation of gene expression

Abstract

The androgen receptor (AR) is a member of the highly conserved group of the class I steroid hormone receptors, a subgroup of the nuclear receptor superfamily of ligand-induced transcription factors. All class I receptors influence the expression of their target genes by binding three-nucleotide spaced partial palindromic repeats of the core 5'-TGTTCT-3' motif. The implication that all class I receptors activate transcription by binding similar DNA motifs, poses the problem of how the in vivo steroid-specificity of transcriptional control is achieved. The AR, however, is able to interact with DNA motifs that are divergent from the classical hormone response elements. We will describe this AR-specific DNA interaction in the context of the general mechanisms that dictate the sequence-specificity of DNA-binding and dimerization of the nuclear receptors. The androgen receptor is the only steroid hormone receptor that is able to interact with response elements that are essentially arranged as a direct repeat of the 5'-TGTTCT-3' monomer binding element. We propose that the DNA-binding domain of the AR can interact with these androgen-specific response elements in a head-to-tail conformation, similar to many other nuclear hormone receptors. The fact that subtle differences in the sequence of response elements can dictate androgen-specific responses is a new and intriguing finding. It creates new possibilities in the research on hormone-selective action and provides a new angle in the search for selective ligands or co-factors that might influence androgen receptor action via either type of DNA motif.