Nuclear receptors regulate diverse biological processes, such as embryonic development, differentiation, and neoplastic conversion, in addition to controlling many metabolic functions. Binding of ligand to a nuclear receptor triggers the orchestrated recruitment and assembly of several transcription coactivators that facilitate nucleosome remodeling and nuclear receptor linking to the basal transcription machinery to achieve the transcriptional enhancement of target genes. Systematic delineation of the functional significance of these transcription coactivators is of considerable importance to the understanding of tissue-/cell-specific regulation of gene expression. We found that germ-line deletion of coactivators PBP, PRIP and PIMT in the mouse results in early- or mid-gestational embryonic lethality, which precludes the functional characterization of these coactivators during late embryonic development, and postnatal growth and maturity. The proposed studies will utilize the floxed PBP, PRIP and PIMT mice we generated for conditional targeted somatic mutagenesis. We will test the hypothesis that the absence of these coactivators interferes with multiple signaling pathways that regulate important biological processes such as energy metabolism, liver regeneration, and carcinogenesis.
Our specific aims will: 1) define the role of 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 (fatty acid oxidation), 3) determine the role and functional relevance of coactivators in the PPAR agonist and CAR agonist-induced nuclear translocation of CAR in mouse liver parenchymal cells and evaluate the mechanisms influencing this translocation, and 4) characterize and establish the coactivator potential of two as yet uncharacterized high molecular weight proteins, PRIC300; PRIC250, isolated from PPAR -interacting cofactor (PRIC) complex, which contain 10 and 13 LXXLL (L, leucine, and X, any amino acid) nuclear receptor-interacting motifs respectively. These studies are expected to generate new information, with implications for human impact, which could provide novel avenues for developing strategies to regulate gene function by altering coactivator activity.
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