Involvement of three glutamine tracts in human androgen receptor transactivation

Abstract

The androgen receptor (AR) possesses a polymorphic polyglutamine tract (polyQ), whose length is inversely correlated with its transcriptional activity. Here, we investigated whether 6 and 5 repetitive glutamine tracts (Q6 and Q5, respectively) in the N-terminal domain of AR also have effects on AR transactivation. In a reporter gene assay using two-tandem repeats of an androgen response element, deletion of glutamine tracts significantly increased AR transactivation in the following order: wild-type < a single deletion of polyQ or Q5 < double deletion of polyQ and Q6 < double deletion of polyQ and Q5 < triple deletion. Deletion of polyQ alone or combined deletion of polyQ and Q5 from an AR mutant lacking the ligand-binding domain, which is constitutively active due to activation function-1, increased AR transactivation. However, the glutamine tracts had no influence on activation function-1 activity, suggesting that the glutamine tracts modulate the binding of AR to DNA. Q5, like polyQ, was found to be involved in the interaction between the NH 2- and COOH-terminal regions of AR (N–C interaction). These results indicate that the inhibitory effects of polyQ and Q5 on AR transactivation are the due, at least in part, to their negative regulation of N–C interaction.