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Transcriptional Interferences between Normal or Mutant Androgen Receptors and the Activator Protein 1—Dissection of the Androgen Receptor Functional Domains¹

Institut National de la Santé et de la Recherche Médicale (J.-M.L., N.P., B.T., V.G., S.L,. C.S)., INSERM U439, Pathologie Moléculaire des Récepteurs Nucléaires, 34090 Montpellier, France; Unité Biochimie Endocrinienne du Développement et de la Reproduction, Hôpital Lapeyronie (N.P., S.L., C.S.), 34295 Montpellier, France; Physiologie Comparée et Endocrinologie (S.F.), CNRS-ERS63, Les Cézeaux, 63177 Aubières, France; Unité Endocrinologie Pédiatrique (C.S.), Hôpital A. de Villeneuve, 34295 Montpellier, France

Address all correspondence and requests for reprints to: Prof. Charles Sultan, INSERM Unité 439, 70 rue de Navacelles, 34090 Montpellier, France. E-mail: chsultan{at}u439.montp.inserm.fr

We investigated the interferences of the normal or mutated androgen receptor with the activator protein-1 (AP-1) by assessing their effects on transcriptional 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 whose transcriptions are activated by androgen and 12-O-tetradecanoyl phorbol-13-acetate, a potent AP-1 activator. The blockade of dephosphorylation by protein phosphatases identifies the protein phosphatases that modulate the AP-1/androgen receptor cross-talk. Using engineered or naturally occurring androgen receptor mutants that are responsible for complete or partial androgen insensitivity syndromes, we defined the subregions involved in the cross-talk of the androgen receptor with the AP-1 factors. First, it appears that the 188 first amino acids of the N-terminal domain of the androgen receptor are necessary to obtain a full transrepression. Second, a functional and intact ligand binding domain is critical for the modulation of androgen/AP-1 pathway interactions. Third, normal DNA binding capacity of the androgen receptor is not required. Two mutants at positions 568 and 581 of the DNA binding domain demonstrate that the transactivation and transrepression functions of the androgen receptor can be dissociated. Collectively, these data indicate that several segments of the androgen receptor are involved in cross-talk with the AP-1 pathway. Mutations within the DNA binding domain of the androgen receptor highly impair these interferences.

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