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 effec ts in vivo by binding and activating their cognate receptors. These intrace llular receptors are transcription factors that can bind specific DNA seque nces, called hormone response elements, located near the target genes. Alth ough the androgen receptor (AR) and the glucocorticoid receptor (GR) bind t he same consensus DNA sequence. androgen-specific responses can be achieved by non-conventional androgen response elements (AREs). Here we determine t he specificity mechanism of such a selective element recently identified in the first exon of the human gene for secretory component (se ARE). This sc ARE consists of two receptor-binding hexamers separated by three nucleotid es. The DNA-binding domains of the AR and GR both bind the sc ARE, but, alt hough the AR Fragment dimerizes on the element, the GR fragment does not. C omparing 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 he xamer and more precisely by the presence of a G residue at position -3, rel ative to the central spacer nucleotide. Inserting a G at this position chan ged a non-selective element into an androgen-selective one. We postulate th at 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 bin ding 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 indicate d by the DNA-binding characteristics of receptor fragments in which the dim erization interfaces were swapped. In addition, the flanking and spacer seq uences seem to affect the functionality of the sc ARE.