Abstract
Recent discovery of nuclear retinoid receptors revealed that a variety of retinoid (vitamin A) action is exerted by the nuclear receptors-mediated gene expression. Nuclear retinoid receptors are classified into two classes, all-trans-retinoic acid receptors (RARα, β and γ) and retinoid-X-receptors (RXRα,β and γ). Ho- mo- and hetro-dimers of RAR and RXR bind to specific retinoid response elements (RARE and RXRE) located in the target gene promoters. These response elements are composed of two direct repeated AGGTCA motifs (or related motif) spaced by 1,2 and 5bp (DR 1,2 and 5). Based upon these observations, the molecular mechanisms of retinoid actions were considered from different experimental approaches. By extending our previous findings in unusual estrogen response elements, other classes of retinoid response elements have been identified from systematic studies. Using animal models of various status of retinoid, vitamin D and thyroid hormone, we found that the gene expression of RARβ our of three RARs is positively regulated at transcriptional level by retinoid, but not vitamin D and thyroid hormone. In the contrast, the gene expression of RXRβ (positive) and RXRγ (negative) is regulated transcriptionally and post-transcriptionally by only thyroid hormone. Furthermore, the effects of these three ligands on the gene expression of cellular retinoid binding proteins are under investigation. In addition, isomerization of active form of retinoic acids and the functional domain of RAR and RXR with special attention to phosphorylation are also studied. Thus, taken together, these studies may clarify a part of the molecular mechanisms of retinoid actions.
