Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains

The androgen and glucocorticoid hormones evoke specific in vivo responses b y activating different sets of responsive genes. Although the consensus seq uences of the glucocorticoid and androgen response elements are very simila r, this in vivo specificity can in some cases be explained by differences i n DNA recognition between both receptors. This has clearly been demonstrate d for the androgen response element PB-ARE-2 described in the promoter of t he rat probasin gene. Swapping of different fragments between the androgen- and glucocorticoid-receptor DNA-binding domains demonstrates that (i) the first Zn-finger module is not involved in this sequence selectivity and (ii ) that residues in the second Zn-finger as well as a C-terminal extension o f the DNA-binding domain from the androgen receptor are required. For speci fic and high-affinity binding to response elements, the DNA-binding domains of the androgen and glucocorticoid receptors need a different C-terminal e xtension. The glucocorticoid receptor requires 12 C-terminal amino acids fo r high affinity DNA binding, while the androgen receptor only involves four residues. However, for specific recognition of the PB-ARE-2, the androgen receptor also requires 12 C-terminal residues. Our data demonstrate that th e mechanism by which the androgen receptor binds selectively to the PB-ARE- 2 is different from that used by the glucocorticoid receptor to bind a cons ensus response element. We would like to suggest that the androgen receptor recognizes response elements as a direct repeat rather than the classical inverted repeat.