Modulation of Estrogen Receptor-α Transcriptional Activity by the Coactivator PGC-1

Abstract A transcriptional coactivator of the peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ-coactivator-1(PGC-1) interacts in a constitutive manner with the hinge domain of PPARγ and enhances its transcriptional activity. In this study we demonstrate that PGC-1 is a coactivator of estrogen receptor-α (ERα)-dependent transcriptional activity. However the mechanism by which PGC-1 interacts with ERα is different from that of PPARγ. Specifically, it was determined that the carboxyl terminus of PGC-1 interacts in a ligand-independent manner with the ERα hinge domain. In addition, an LXXLL motif within the amino terminus of PGC-1 was shown to interact in an agonist-dependent manner with the AF2 domain within the carboxyl terminus of ERα. The ability of PGC-1 to associate with and potentiate the transcriptional activity of an ERα-AF2 mutant that is unable to interact with the p160 class of coactivators suggests that this coactivator may have a unique role in estrogen signaling. It is concluded from these studies that PGC-1 is a bona fideERα coactivator, which may serve as a convergence point between PPARγ and ERα signaling.