Functions of intracellular lipid-binding proteins

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): The vitamin A metabolite retinoic acid (RA) regulates gene transcription by activating two members of the nuclear receptor family of ligand-activated transcription factors: the retinoic acid receptors (RARs) and the peroxisome proliferator activated receptor ? (PPAR?). The partitioning of RA between its receptors is controlled by the intracellular lipid binding proteins CRABP-II, which delivers the hormone to RAR, and FABP5, which shuttles it to PPAR?. Consequently, the relative expression levels of CRABP-II and FABP5 determine the pathway through which RA activates transcription, the spectrum of genes whose expression is regulated by RA, and the biological responses to this hormone in different cells. RA is thus closely involved in regulation of multiple biological activities in health and in disease states including cancer and the metabolic syndrome. Studies described in this application will investigate the involvement of RA and its binding proteins and nuclear receptors in adipocyte biology and in regulating mammary carcinoma growth. Specifically, we propose to: 1) understand how RA maintains the phenotype of preadipose cells and to examine whether inhibition of adipogenesis by RA contributes to the remarkable ability of the hormone to counteract diet-induced obesity; 2) investigate the possibility that development of some cancers originates from improper RA signalling derived from dysregulation of the FABP5/CRABP-II ratio, especially arising from upregulation of FABP5 in tumors. We propose to shed light on the mechanisms that lead to increased expression of FABP5 in mammary tumors, examine whether FABP5 functions as an oncogene, and explore the possibility that downregulation of FABP5 will divert RA from PPAR? to RAR to inhibit tumor growth.