REGULATORY MECHANISMS OF SRC FAMILY COACTIVATION IN ADIPOGENESIS

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Steroid receptors regulate the expression of a myriad of target genes involved in metabolism, development, and reproduction. Nuclear receptors (NRs) are activated, usually by ligands, and relocate to specific DMA binding sites at target gene promoters where they accumulate an array of coactivators (or corepressors) that carry out the series of transcriptional substeps required for modulating gene expression. The SRC/p160 family of coactivators appears to play a fundamental role in this latter regard. We hypothesize that NRs and their attendant coactivators have evolved as the primary regulators of adipocyte devevelopment and of metabolic pathways in fat cells and other metabolic tissues. Toward the goal of elucidating these pathways that control lipid and carbohydrate metabolism, we plan to carry out investigations of the genetic, structural, regulatory and metabolic functions of SRC family coactivators in cell extracts, in cells and in animals. Specific Aim 1: Definition of SRC-3 target genes regulated during adipocyte differentiation and study of the epigenetic regulators of SRC-3 function in fat cells. Specific Aim 2: Study of the role of protein stabilization of SRC-3 during adipocyte differentiation. Specific Aim 3: Characterization of adipocyte SRC-coactivator complexes. Specific Aim 4: Study of the specific contribution of each of the three p160 SRC family members and COUPTF-II in the cascade of events responsible for the adipogenic process. To accomplish these tasks, we will employ an integrative methodological approach to prove our hypothesis which uses the technoloigies of cellular biology, biochemistry, physical chemistry, physical chemistry, microscopy, nucleic acid and transgenic biology, and genetics and animal physiology. This information will lead to a much greater understanding of the contributions of coactivator biology to adipocyte function and should uncover new intervention points that would aid in the design of novel therapies for metabolic disorders in humans.