REGULATORY MECHANISMS OF SRC FAMILY COACTIVATION IN ADIPOGENESIS

Baylor College Of Medicine, Houston TX

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Abstract

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