Retinoids play key roles in regulating cell proliferation and differentiation and are used as therapeutic agents in clinical settings ranging from dermatological disorders to cancer. Signaling by these hormones is mediated by two classes of ligand-activated transcription factors, the retinoic acid- and the retinoid X-receptors (RAR and RXR), which are activated by all trans- and 9 cis-retinoic acids, respectively (RA and 9cra). Because of its unique ability to heterodimerize with other nuclear receptors, RCR is involved in multiple signaling pathways and is thus sometimes termed a 'master regulator'. RXR is also unique in that, in the absence of 9cRA, it sequesters itself into transcriptionally inactive tetramers. Hence, RXR acts as an 'auto-silencer', and the first step in its activation seems to compromise ligand-induced dissociation of tetramers into active dimers and monomers. This application proposes to delineate the roles of the oligomerization behavior of RxR and the presence of various cognate ligands in governing the distribution of RXR between the multiple molecular complexes in which it may be involved in vivo. The functional consequences of the physical-chemical properties of the various RCR-containing oligomers for the transcriptional activity of RXR in cells, and the possible functional outcomes of DNA-binding by RXR tetramers will then be explored. In addition to retinoid receptors, two intracellular binding proteins for RA (CRABP-I and CRABP-II) are known to exist. The exact roles of CRABPs in the biology of RA and the functional differences between the two isoforms are not well defined. Our recent studies suggest that CRABP-II, but not CRABP-1, directly 'channels' retinoic acid to RAR, thereby enhancing the transcriptional activity of this receptor. These observations point at a novel role for CRABP-II in regulating retinoid signaling. We propose to study the CRABP-II.RAR interactions that allow for channeling of RA between them, and to address the physiological significance of these interactions by investigating the effect of CRABP-II on RA-induced stem cell differentiation. Overall, these studies are designed to clarify the factors that modulate the multiple interactions of retinoic nuclear receptors and to obtain insights into the mechanisms by which signaling by retinoids is regulated.
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