Retinoic acid receptors functions

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

In addition to the receptors mentioned in A, the family of steroid receptors also includes the product of the oncogene erb-A (see p. 398), the receptor for the environmental toxin dioxin, and other proteins for which a distinct hormone ligand has not been identified (known as orphan receptors ). Several steroid receptors—e. g., the retinoic acid receptor-form functional heterodimers with orphan receptors. 

Retinoid action depends on binding to both cytosolic and nuclear retinoic acid receptors (RARs). RARs have distinct DNA and retinoid-binding domains, and they function as pairs and bind to the retinoic acid receptor element (RARE) to regulate transcriptional activity. 

Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

The PPAR-RXR complex binds to specific DNA response elements (PPREs composed of two hexanucleotide direct repeats) in gene promoters and functions as a transcription factor, which can be activated by either RXR- or PPAR-specific ligands. The consensus site for PPAR-RXR binding is a direct repeat of two -AGGTCA- sequences with a single nucleotide spacer (a DR1 response element). However, DR1 elements may also bind other complexes, including RAR (retinoic acid receptor)/RXR heterodimers and RXR homodimers (25). Further specificity for binding of PPARs may be provided by sequences that flank the DR1 site (26). 

Nagpal, S., Athanikar, J., and Chandraratna, R.A., Separation of transactivation and API antagonism functions of retinoic acid receptor alpha, J. Biol. Chem., 270, 923, 1995. 

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

The structural design of retinoic acid receptors explains, at least in part, the pleiotropy of this class of receptors. It is a consequence of the combinatorial possibilities offered by heterodimerization. The many different functional units that can be formed by heterodimerization make it understandable why so many different gene response elements can be recognized. This, and a distinct spatiotemporal pattern of expression, both in the developing embryo and in differentiated tissues, suggests that each RAR and RXR isoform and each heterodimer formed may have a unique function. Pierre Chambon has directed attention to the large repertoire of combinatorial arrangements. These combina-... 

Another forefront technique to improve the function of the stratum corneum and enhance barrier repair in dry skin is the use of epidermal differentiation. A number of hormone receptors for epidermal differentiation have been identified. This family of receptors includes retinoic acid receptors, the steroid receptors, the thyroid receptors, the Vitamin D receptors, the peroxisome proliferator-activated receptors, the farnesol-activated receptors, and the liver-activated receptors. It is reported that these transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Examples of ligands for the last three transcription factors are fatty acids for the peroxisome proliferator-activated receptor, famesol for the farnesol-activated receptor, and hydroxylated cholesterol derivatives for the liver-activated receptor. The stimulation of epidermal differentiation stimulated the synthesis of involucrin, filaggrin, and the enzymes of the ceramide synthesis pathway (74). 

Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. 1993. Function of retinoic acid receptor gamma in the mouse. Cell 73, 643-658. 

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