FUNCTIONS OF INTRACELLULAR LIPID-BINDING PROTEINS

描述(申请人提供)：膳食维生素A和长链脂肪酸(LCFA)可以产生信号分子，通过它们调节多个基因的转录速率来控制细胞过程。这些活性是由称为核激素受体的配体诱导的转录因子介导的。维生素A代谢产物维甲酸(RA)通过激活核受体RAR和RXR来调控转录。最具特征的介导LCFA及其衍生物转录活性的受体是TenNet PPAR。除了核受体，RA和LCFA在细胞中都与被称为细胞内脂结合蛋白(ILBP)的蛋白质家族成员联系在一起。RA与细胞维甲酸结合蛋白(CRABP-I和CRABP-II)结合，而LCFA与多种形式的脂肪酸结合蛋白(FABP)结合。近年来，核受体的作用机制日益清晰。相反，虽然人们普遍认为iLBP在其配体的增溶和运输中发挥作用，但不同iLBP亚型所起的具体作用仍然知之甚少。我们以前的研究导致了CRABP-II的特定功能的确定。我们证明了CRABP-II(但不是CRABIP-I)通过与RAR直接相互作用来调节RA的转录活性。我们最近进一步发现，一些FABP可以调节PPAR的转录活性，表明除了CRABP-II之外，iLBP还参与其配体的转录活性。本申请的目的是研究iLBP作为转录共调节因子的作用。为此，我们建议描述iLBP调节核受体配体依赖活性的机制，并阐明iLBP存在对细胞内核受体生物学活性的功能影响。在两个特定目标下的研究中，我们建议阐明CRABP-II参与RAR的细胞活动，并探讨FABP在调节PPAR转录活性中的作用。

DESCRIPTION (provided by applicant): Dietary vitamin A and long chain fatty acids (LCFA) give rise to signaling molecules that control cellular processes by virtue of their ability to modulate the rates of transcription of multiple genes. These activities are mediated by ligand inducible transcription factors known as nuclear hormone receptors. The vitamin A metabolite retinoic acid (RA) governs transcription by activating the nuclear receptors RAR and RXR. The best characterized receptors to mediate the transcriptional activities of LCFA and their derivatives are tenned PPAR. In addition to nuclear receptors, both RA and LCFA associate in cells with members of the family of proteins known as intracellular lipid-binding proteins (iLBP). RA binds to cellular retinoic acid binding proteins (CRABP-I and CRABP-II), while LCFA associate with multiple forms of fatty acid binding proteins (FABP). The mechanisms of action of nuclear receptors have become increasingly clear in recent years. In contrast, while it is generally believed that iLBPs function in solubilization and trafficking of their ligands, the specific roles served by the different iLBP isotypes remain poorly understood. Our previous studies led to the identification of a specific function for CRABP-II. We demonstrated that CRABP-II (but not CRABIP-I) modulates the transcriptional activity of RA through direct interactions with RAR. We recently found further that some FABPs can modulate the transcriptional activities of PPARs, demonstrating that iLBPs other than CRABP-II also participate in the transcriptional activities of their ligands. The goal of this application is to examine the roles of iLBPs as transcriptional co-regulators. To this end we propose to delineate the mechanisms by which iLBPs modulate the ligand-dependent activities of nuclear receptors, and to clarify the functional consequences of the presence of iLBPs for the biological activities of nuclear receptors in cells. In studies outlined under 2 specific aims we propose to clarify the involvement of CRABP-II in the cellular activities of RAR, and to explore the roles of FABPs in regulating the transcriptional activities of PPARs.