Sophia Y. Tsai

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 their association with steroid receptor coactivators (SRCs) upon binding to 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 analyzed. First, we show that SRC-1 is a modular coactivator that possesses intrinsic transcriptional activity when tethered to DNA and that it harbors two distinct activation domains, AD1 and AD2, needed for the maximum coactivation function of steroid receptors. We also demonstrate that SRC-1 interacts with both the amino-terminal A/B or AF1-containing domain and the carboxyl-terminal D/E or AF2-containing domain of the steroid receptors. These interactions are carried out by multiple regions of SRC-1, and they are relevant for transactivation. In addition to the inherent histone acetyltransferase activity of SRC-1, the presence of multiple receptor-coactivator interaction sites in SRC-1 and its ability to interact with components of the basic transcriptional machinery appears to be, at least in part, the mechanism by which the individual activation functions of the steroid receptors act cooperatively to achieve full transcriptional activity.

The Structure and Regulation of the Natural Chicken Ovomucoid Gene

The molecular mechanism by which steroid hormones regulate specific gene expression has been an area of acute interest during the past several years. One particularly attractive model system for studying this hormonal regulation has been the hen oviduct (O’Malley et al. 1969). A number of laboratories, in addition to our own, have utilized this model system for investigations of eucaryotic molecular biology (Oka and Schimke 1969; Palmiter and Schimke 1973; Palmiter et al. 1976; Cox 1977; Hynes et al. 1977; Garapin et al. 1978b; Mandel et al. 1978). Administration of estrogen to the newborn chick stimulates oviduct growth and differentiation and results in the appearance of a number of new specific intracellular proteins (O’Malley et al. 1969; Hynes et al. 1977; Palmiter 1973; Chan et al. 1973; Harris et al. 1973, 1975; Sullivan et al. 1973; O’Malley and Means 1974). The synthesis of one of these proteins, ovalbumin, has been studied extensively. Ovalbumin mRNA has been purified (Rosen et al. 1975), and a full-length dsDNA copy synthesized (Monahan et al. 1976b) and cloned in a bacterial plasmid (McReynolds et al. 1977). More recently, ovalbumin genomic DNA sequences have been isolated from restriction enzyme digests of hen DNA and cloned (Woo et al. 1978). The other three major proteins under estrogenic control in the oviduct tubular gland cell, ovomucoid, conalbumin and lysozyme, have been less extensively studied (Palmiter 1972; Hynes et al. 1977).