Negative androgen-response elements in androgen target genes

Genes that are positively regulated by androgen receptor (AR) contain the positive androgen-response element (pARE) in their proximal or/and distal promoter regions. Similarly, genes that are negatively regulated by AR contain the negative androgen-response element (nARE). In this chapter, we review our work on identification and characterization of nARE. We identified seven nAREs in the negative androgen-response region in the TGF-β1 promoter. Each nARE is composed of 15 nucleotides and mediates androgen-dependent inhibition of transcription. The 5′ portions of nAREs are highly conserved and resemble core half-sites in pAREs. The nAREs interacted weakly with AR DNA-binding domain (AR DBD) in gel shift assays. Mutations on the conserved nucleotides in the nARE abolished its interaction with the AR DBD and abolished its inhibition of androgen-driven transcription, suggesting that nARE/AR interaction is essential for nARE-mediated inhibition of transcription. Taken together, these findings indicate that the AR negatively regulates the expression of its target genes via a negative androgen-response region composed of multiple nAREs.