Transcriptional interferences between normal or mutant androgen receptors and the activator protein 1 - Dissection of the androgen receptor functional domains

We investigated the interferences of the normal or mutated androgen recepto r with the activator protein-1 (AP-1) by assessing their effects on transcr iptional activity in CV-1 cells. A luciferase reporter gene was constructed downstream from either a promoter for the mouse vas deferens protein, or a trimerized 12-O-tetradecanoyl phorbol-13-acetate-response element site who se transcriptions are activated by androgen and 12-O-tetradecanoyl phorbol- 13-acetate, a potent AP-1 activator. The blockade of dephosphorylation by p rotein phosphatases identifies the protein phosphatases that modulate the A P-1/androgen receptor cross-talk. Using engineered or naturally occurring a ndrogen receptor mutants that are responsible for complete or partial andro gen insensitivity syndromes, we defined the subregions involved in the cros s-talk of the androgen receptor with the AP-1 factors. First, it appears th at the 188 first amino acids of the N-terminal domain of the androgen recep tor are necessary to obtain a full transrepression. Second, a functional an d intact ligand binding domain is critical for the modulation of androgen/A P-1 pathway interactions. Third, normal DNA binding capacity of the androge n receptor is not required. Two mutants at positions 568 and 581 of the DNA binding domain demonstrate that the transactivation and transrepression fu nctions of the androgen receptor can be dissociated. Collectively, these da ta indicate that several segments of the androgen receptor are involved in cross-talk with the AP-1 pathway. Mutations within the DNA binding domain o f the androgen receptor highly impair these interferences.