Members of the peroxisome proliferator-activated receptor subfamily (PPARalpha, PPARgamma, and PPARdelta) play a central role in lipid metabolism/energy homeostasis, adipocyte differentiation, and cancer. After recognizing their ligands, nuclear receptors translocate to the nucleus where they bind to specific DNA elements and in concert with coactivators modulate gene expression. Elucidation of the mechanism(s) by which nuclear receptor coactivators enhance gene expression in a cell-gene- (possibly species-) specific manner is of paramount importance. Using PPAR as bait in a yeast two-hybrid screen, we cloned and characterized PBP and PRIP as nuclear receptor coactivators, and PIMT as PRIP-binding protein. Based on limited evidence derived from gene knockout mouse models, coactivators can be redundant (nonessential and compatible with life) for the function of certain but not all nuclear receptors, and nonredundant (essential for life) for the functional integrity of many transcription factors, thus their deletion leads to embryonic lethality. Based on our findings, we hypothesize that the essential/nonredundant coactivators, such as PBP and PRIP, interact with many transcription factors in addition to nuclear receptor-, and coactivator-associated proteins, in a cell and gene specific manner. We further hypothesize that the site- and time-specific gene targeting in the mouse of these essential nonredundant coactivators would lead to disruption/disintegration of the transcriptional coactivator complexes, leading to developmental and functional abnormalities.
Our specific aims are to: 1) Investigate the functional role of PBP and PRIP genes, singly or in combination, in metabolic and Iigand-dependent regulation of hepatic gene expression in vivo; 2) Determine whether PRIP-interacting protein PIMT is an essential (non-redundant), or nonessential (redundant) cofactor and then study the functional perturbations caused by PIMT null mutation; and 3) Elucidate molecular mechanisms by which PBP, PRIP and PIMT affect gene expression in vivo and in vitro. These studies not only permit the development and identification of model systems, but also are expected to generate valuable insights into the molecular complexity and the functional implications of coactivators in liver development, functional homeostasis and cancer.
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