A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity

Estrogen receptors ER alpha and ER beta are members of the family of nuclear hormone receptors and act as ligand-inducible transcriptional factors, which regulate the expression of target genes on binding to cognate response elements. We report here the characterization of steroid receptor coactivator-3 (SRC-3), a coactivator of nuclear receptor transcription that is a member of a family of steroid receptor coactivators that includes SRC-1 and transcription intermediate factor-2, SRC-3 enhanced ER alpha and progesterone receptor-stimulated gene transcription in a ligand dependent manner, but stimulation of ER beta-mediated transcription was not observed. Protein-protein interaction assays, including real-time interaction analyses with BIAcore, demonstrated that the affinity of the ERa interaction with SRC-3 was much higher than that observed for the ERP interaction with SRC-S. Mutational analysis suggests a potential interplay between the transactivation function-1 and -2 do mains of ER alpha and SRC-3, Furthermore, an intrinsic transactivation function was observed in the C-terminal half of SRC-3. Finally, SRC-3 was differentially expressed in various tissues and, among several tumor cells examined, was most abundant in the nuclear fraction of MCF-7 breast cancer cells. Therefore, SRC-S, a third member of a family of steroid receptor coactivators, has a distinct tissue distribution and intriguing selectivity between ER alpha and ER beta.