THE STEROID-RECEPTOR COACTIVATOR-1 CONTAINS MULTIPLE RECEPTOR INTERACTING AND ACTIVATION DOMAINS THAT COOPERATIVELY ENHANCE THE ACTIVATION FUNCTION-1 (AF1) AND AF2 DOMAINS OF STEROID-RECEPTORS

Steroid receptors are ligand-inducible transcription factors, and thei r association with steroid receptor coactivators (SRCs) upon binding t o DNA is necessary for them to achieve full transcriptional potential. To understand the mechanism of SRC-1 action, its ability to interact and enhance the transcriptional activity of steroid receptors was anal yzed. First, we show that SRC-1 is a modular coactivator that possesse s intrinsic transcriptional activity when tethered to DNA and that it harbors two distinct activation domains, AD1 and AD2, needed for the m aximum coactivation function of steroid receptors. We also demonstrate that SRC-1 interacts with both the amino-terminal A/B or AF1-containi ng domain and the carboxyl-terminal D/E or AF2-containing domain of th e steroid receptors, These interactions are carried out by multiple re gions of SRC-1, and they are relevant for transactivation, In addition to the inherent histone acetyltransferase activity of SRC-1, the pres ence of multiple receptor-coactivator interaction sites in SRC-1 and i ts ability to interact with components of the basic transcriptional ma chinery appears to be, at least in part, the mechanism by which the in dividual activation functions of the steroid receptors act cooperative ly to achieve full transcriptional activity.