REGULATION AND FUNCTION OF NUCLEAR RECEPTOR COACTIVATORS

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Nuclear receptors mediate many hormone actions that regulate important physiological processes in human and in higher eukaryotic organisms. The binding of the lipophilic hormones to nuclear receptors triggers conformational changes in the receptors, leading to transcriptional activation of the receptors and target gene stimulation. Recent studies have led to the discovery of several nuclear receptor cofactors that can modulate the transcriptional activity of nuclear receptors. These cofactors are potential regulators of hormone actions. Two main classes of nuclear receptor cofactors have been identified: corepressors that promote transcriptional repression by unliganded receptors and coactivators that enhance transcriptional activation by liganded receptors. The event of hormone-binding is believed to trigger dissociation of corepressors from the receptors and recruitment of coactivators to the receptors. The applicant's laboratory has recently identified and cloned a new member of the nuclear receptor coactivator family termed RAC3, which is also known as AIB1, p/CIP, ACTR, and TRAM-1. The sequence of RAC3 is closely related to that of SRC-1 and TIF2, two most potent nuclear receptor coactivators. Currently, the biological relevance of RAC3 in hormone signaling is still unclear, but importantly, RAC3 was found to associate strongly with CBP/p300 in vivo and to be overexpressed in several human cancer cells, suggesting a crucial role of RAC3 in the regulation of cell growth and proliferation. In order to better understand the mechanism of RAC3 action and its role in hormone signaling, in this study we will continue to investigate the structural and functional relationship of the RAC3 protein. We will also investigate the role of RAC3 in retinoic acid (RA)-mediated stem cell differentiation and control of gene expression. Finally, we will identify and characterize new RAC3-interacting proteins, thereby substantially expanding our understanding of the biological function of RAC3 in living cells. Together, these studies are critical for understanding the function of the nuclear receptor coactivator RAC3 and its role in hormone signaling. The functional interaction between nuclear receptors and coactivators will serve as a model for understanding transcriptional regulation of other transcriptional activators. This project represents an important aspect of our long-term directions and the results will provide insights for development of future therapeutics that can control hormone- regulated and -dysregulated cell growth and proliferation.