Nuclear receptors regulate diverse biological processes such as embryonic development, differentiation, and neoplastic conversion. In addition, they control many critical metabolic functions. Binding of ligand to a cognate nuclear receptor triggers the recruitment and assembly of several transcriptional coactivators that facilitate nucleosome remodeling and nuclear receptor linking to the basal transcription machinery to enhance transcription of target genes. Over the years, we and others have identified a number of nuclear receptor coactivators for members of peroxisome proliferator-activated receptor (PPAR) subfamily. These include SRC- 1, PBP/MED1, PRIP (NCoA6), PRIP-interacting protein PIMT (NCoA6IP), PRIC285, and PRIC320 among others. This application will seek to determine the physiological functions of three coactivators, namely PBP, PRIP and PIMT which, when globally knocked out (germ-line deletion), cause embryonic lethality. We generated floxed PBP, PRIP and PIMT mice for conditional mutagenesis, to determine the biological roles of these coactivators. We will test the hypothesis that the absence of certain coactivators or select sets of coactivators in liver cells interferes with multiple signaling pathways that regulate energy metabolism, liver regeneration, and liver carcinogenesis. We will address the following specific aims to: 1) define the role of coactivators PBP, PRIP and PIMT in liver regeneration and liver carcinogenesis;2) investigate the functional roles of coactivators PBP, PRIP and PIMT in nuclear receptor PPAR and PPAR signaling mechanisms necessary for hepatic energy metabolism;3) determine the role of coactivators in the PPAR agonist and CAR agonist-induced nuclear translocation of CAR in mouse liver, and evaluate the mechanisms influencing this translocation;4) establish the coactivator potential of two as yet uncharacterized high molecular weight proteins, PRIC300 and PRIC250, isolated from PPAR-interacting cofactor (PRIC) complex. The proposed studies are highly relevant with implications for human impact and are expected to generate new information on the role of coactivators in liver development, regeneration and liver cancer development. These studies could provide a basis for testing strategies to regulate gene expression by altering coactivator gene function to influence biological processes such as cancer.
Nuclear receptors, together with several partner proteins called coactivators, regulate development, reproduction, and many metabolic functions that lead to obesity, type 2 diabetes, cardiovascular diseases and cancer. The proposed studies, using mice genetically designed for the organ specific disruption of a coactivator gene, are expected to enhance our understanding of the functions of these promiscuous nuclear receptor partners. They should provide a rational basis for testing strategies to regulate gene expression.
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