Androgen-receptor-specific DNA binding to an element in the first exon of the human secretory component gene

Androgens and glucocorticoids are steroid hormones, which exert their effects in vivo by binding and activating their cognate receptors. These intracellular receptors are transcription factors that can bind specific DNA sequences, called hormone response elements, located near the target genes. Although the androgen receptor (AR) and the glucocorticoid receptor (GR) bind the same consensus DNA sequence, androgen-specific responses can be achieved by non-conventional androgen response elements (AREs). Here we determine the specificity mechanism of such a selective element recently identified in the first exon of the human gene for secretory component (sc ARE). This sc ARE consists of two receptor-binding hexamers separated by three nucleotides. The DNA-binding domains of the AR and GR both bind the sc ARE, but, although the AR fragment dimerizes on the element, the GR fragment does not. Comparing the affinities of the DNA-binding domains for mutant forms of the sc ARE revealed that dimeric GR binding is actively excluded by the left hexamer and more precisely by the presence of a G residue at position -3, relative to the central spacer nucleotide. Inserting a G at this position changed a non-selective element into an androgen-selective one. We postulate that the AR recognizes the sc ARE as a direct repeat of two 5'-TGTTCT-3'-like core sequences instead of the classical inverted repeat. Direct repeat binding is not possible for the GR, thus explaining the selectivity of the sc ARE. This alternative dimerization by the AR on the sc ARE is also indicated by the DNA-binding characteristics of receptor fragments in which the dimerization interfaces were swapped. In addition, the flanking and spacer sequences seem to affect the functionality of the sc ARE.