The effects of natural retinoic acids [RA, 9-cis-RA, 3,4-didehydroRA (DDRA) and 4-oxo-RA] in the regulation of discrete sets of target gens are produced through a cascade of events mediated by the retinoid family of nuclear receptors (RARs and RXRs). Ligand binding, receptor dimerization and transcriptional complex formation are three main steps in the display of the biological activity of these retinoids. Following our development of an analytical procedure to study the homo- and hetero- dimerization of RARs/RXRs and complexing with RA response elements (RARE), we propose to unravel the intricate mechanisms of receptor- mediated molecular events by determining in a quantitative manner the receptor subtype selectivity and ligand specificity in ligand/receptor, receptor protein-protein, and protein-DNA interactions. The selectivity in binding produced by single ligands and combinations of ligands for dimers of multiple receptors isoforms will be elucidated and further verified by transcriptional activation assays in CV-1 cells. We will examine whether the optimal physical conditions established in the above interactions are physiological relevant with respect to the kinetics of binding of Ras to RARs/RXRs under monomer, dimer, and dimer-RE forming conditions. Since DDRA (vitamin A2 acid) and 4-oxo-RA (the major cellular metabolite of RA) display selective biological activities and bind RARs/RXRs, we will elucidate, through separate set of experiments, their specific participating roles in the central scheme of RA/9-cis-RA-RAR/RXR-RE mediated transcriptional complex formation and gene activation. These studies will help unravel the key steps in the receptor-mediated molecular mechanism of action of retinoids in reference to the discrete genomic functions of natural Ras in the control of cell differentiation and tumorigenesis.
| Shealy, Y Fulmer; Riordan, James M; Frye, Jerry L et al. (2003) Inhibition of papilloma formation by analogues of 7,8-dihydroretinoic acid. J Med Chem 46:1931-9 |
