par Monge, Audrey;Jagla, Monika;Lapouge, Gaëlle ;Sasorith, S;Cruchant, Marion;Wurtz, J-M;Jacqmin, Didier;Bergerat, J-P;Céraline, Jocelyn
Référence Cellular and molecular life sciences, 63, 4, page (487-497)
Publication Publié, 2006-02
Référence Cellular and molecular life sciences, 63, 4, page (487-497)
Publication Publié, 2006-02
Article révisé par les pairs
Résumé : | Missense mutations in the androgen receptor (AR) contribute to the failure of hormonal therapy for prostate cancer (PCa), but the underlying molecular bases remain uncharacterized. Here, we describe a new AR variant found in a hormone-refractory metastatic PCa, in which threonine 575 in the DNA binding domain, and threonine 877 in the ligand-binding domain, were both replaced by an alanine. Using gene reporter assays, we demonstrate that the T575A mutation weakened transcriptional activity from promoters containing AR-specific responsive elements, while activity from promoters with AR-non-specific elements was enhanced. Data from gel shift experiments revealed a preferential binding of the T575A mutant to AR-non-specific motifs. We demonstrate that the two mutations T575A and T877A cooperate to confer new functional properties on the AR, and that the mutant AR functions simultaneously as a promiscuous AR due to the T877A mutation, and an unfaithful AR due to the T575A mutation. |