and specific aims): Retinoic acid (RA), one of the most potent natural forms of vitamin A, plays an important role in the growth and differentiation of both normal and transformed cells. Recently the retinoic acid receptors (RAR-a, -b. and -g) and retinoid X receptors (RXR-a, -b and -g) have been identified and demonstrated to modulate the action of retinoids by transcriptionally regulating gene expression. Little information is available concerning the structure of the ligand binding domain of RARs. Since each of the RARs have been demonstrated to have different affinities for a large number of retinoids, it appears that the three dimensional conformation of the retinoid binding site of each RAR is somewhat unique. In addition, a number of studies have indicated that each RAR type regulates at least some specific non- overlapping functions. We have previously demonstrated that two amino acid residues, Arg269 and Lys220, of RAR-b are critical for RA binding using site- directed mutagenesis. In addition, during the process of our mutagenesis studies we have created a unique retinol-specific RAR-b (R269Q). To further understand the unique structural and functional features of RARs we plan to (1) identify functionally important amino acids in the ligand binding site of each RAR by continuing our ongoing site-directed mutagenesis studies and (2) use the mutant retinol specific RAR-b receptor, R269Q, to determine unique functions or targets of RAR-b isoforms. These studies will provide us important information concerning the functional importance of amino acid residues in the ligand binding site of each RAR, provide useful new mutant receptors to probe the unique functions of each RAR and using already available mutant receptor of RAR-b useful information related to the functions of RAR-b isoforms. An understanding of these unique features of the RARs will contribute to the ultimate development of retinoids targeted to a specific RAR to elicit specific functions in the body potentially for dermatological and/or cancer chemotherapeutic or chemopreventive treatments.
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