Retinoic acids display pleiotropic biological activities which stem from their ability to regulate the rates of transcription of multiple target genes. These compounds play key roles in differentiation and proliferation of cells, are potent inhibitors of carcinogenesis, and are currently used as therapeutic and preventive agents in several clinical settings, ranging from dermatological disorders to cancer. Signalling by these hormones is mediated by two classes of nuclear receptors: the retinoid X receptors (RXR), and the retinoic acid receptors (RAR). RXR is of particular importance, because it also serves as an obligatory heterodimerization partner for a number of other nuclear receptors, and is thus central for multiple signalling events that converge at the genome. In addition to retinoid receptors, retinoic acid binds in cells to members of the family of intracellular lipid binding proteins (iLBP) known as cellular retinoic acid-binding proteins (CRABP). The overall goal of this work is to delineate the molecular mechanisms underlying the transcriptional activities of lipophilic hormones such as retinoic acids, and to clarify the functional consequences of these activities. The current proposal has three specific aims. (1) To understand the factors that control the distribution of RXR between the various oligomers through which it exerts its transcriptional activities, and the role of this receptor in governing the nuclear localization of its heterodimerization partners. (2) Recent observations suggest that RXR, not only acts as a ligand inducible transcription factor, but may also regulate transcription through modulation of DNA geometry. We plan to characterize this novel activity of RXR and to explore its functional significance. (3) Previous work revealed that CRABP-II, as well as two other members of the iLBP family, function by delivering their respective ligands to the nucleus, where they directly deliver them to particular nuclear receptors, thereby significantly enhancing the activities of the receptors. We propose to explore the subcellular localization of CRABP-II, and to delineate the structural features that underlie the ligand-induced nuclear import of iLBPs. The information obtained from these studies is expected to provide new insights into regulatory features of signaling pathways involving transcriptionally active lipophilic hormones, and thus may point at new intervention tools in therapy and prevention of diseases. ? ?
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