Modulation of estrogen receptor-α transcriptional activity by the coactivator PGC-1

A transcriptional coactivator of the peroxisome proliferator-activated receptor-gamma (PPAR gamma), PPAR gamma-coactivator-1(PGC-1) interacts in a constitutive manner with the hinge domain of PPAR gamma and enhances its transcriptional activity. In this study we demonstrate that PGC-1 is a coactivator of estrogen receptor-alpha (ER alpha)-dependent transcriptional activity. However the mechanism by which PGC-1 interacts with ER alpha is different from that of PPAR gamma. Specifically, it was determined that the carboxyl terminus of PGC-1 interacts in a ligand-independent manner with the ER alpha 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 ER alpha. The ability of PGC-1 to associate with and potentiate the transcriptional activity of an ER alpha-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 fide ER alpha coactivator, which may serve as a convergence point between PPAR gamma and ER alpha signaling.