Retinoid Receptors and Response Elements

14-Hydroxyretroretinol, 4-oxoretinol, emd anhydroretinol, as well as possibly other retinoids, edso bind to and activate the RAR family of receptors at physiologiced concentrations, but do not bind to the RXR family. 4-Oxoretinol is formed from edl-trans-retinol in differentiating cells 10% to 15% of intracellular retinol may be oxidized to 4-oxoretinol during an 18-hour period, wheretis there is no formation of tJl-trans-retinoic acid or 9-c/s-retinoic acid. 

4-Oxoretinol induces differentiation of cells in culture (Achkar et td., 1996). In the developing Xenopus embryo, 4-oxoretinaldehyde is the major retinoid, acting tis a precursor of both 4-oxoretinol and 4-oxoretinoic acid, both of which activate the RAR (Blumberg et al., 1996). This developmented role of 

The two families of receptors differ from each other considerahly, and RARs show greater sequence homology with thyroid hormone receptors than with RXRs. RARs act only as heterodimers with RXRs homodimers of RARs have poor affinity for retinoid response elements on DNA. The liganded CRABP(II) enhances the binding of the RAR-RXR heterodimer to response elements on DNA and amplifies the effect of the receptor dimer (Delva et al., 1999). 

RXR forms active homodimers and also form heterodimers with the cal-citriol (vitamin D) receptor (Section 3.3.1), the thyroid hormone receptor, the peroxisome proliferation-activated receptor (PPAR, whose physiological 

In the presence of eill- trans- or 9-c s-retinoic acid, the receptor heterodimers are transcriptional activators. However, the heterodimers will eJso bind to DNA in the absence of retinoic acid, in which case they act as repressors of gene expression (Fujita and Mitsuhashi, 1999). 

RARa and RXR/S have widespread distribution in tissues RAR/8 and RARy are expressed to different extents in different tissues during development. RARa and RXRy have tissue-specific distribution. 

Studies with knockout mutant mice lacking one or another of the retinoid receptors suggest that there is some degree of redundancy or overlap between the receptor subtypes, and that RARy is especiallyimportant in the teratogenic actions of retinoids (Section 2.5.1.1 Mark et al., 1999 Maden, 2000)  

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Gene regulation by tocopherols has mainly been associated with PKC because of its deactivation by a-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, API). A direct participation of the pregnane X receptor (PXR)/ retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element appear in some cases to be implicated as well. The obser ved immunmodulatory function of a-tocopherol may also be attributed to the fact that the release of the proinflammatory cytokine interlukin-l 3 can be inhibited by a-tocopherol via... 

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. 

Figure 5.36 Mechanism of the receptor-mediated induction of CYP4A by a chemical such as the drug clofibrate. The inducer-receptor (PPAR) complex enters the nucleus, binds with RXR, and the complex binds to the receptor response elements in the CYP gene. This induces the production of CYP4A mRNA, which leads to the production of CYP4A protein and functional enzyme. Alternatively, the drug may perturb lipid metabolism leading to increases in a lipid(s), which will bind to the receptor and cause the same response. Abbreviations PPAR, peroxisome proliterator-activated receptor RXR, retinoid X receptor.

The receptor protein (52 kDa) is a member of the steroid hormone receptor superfamily, which has a DNA-binding as well as ligand-binding domain. Another receptor, the retinoid X receptor is also involved, and after binding of the peroxisome proliferator, the two receptors form a heterodimer. This binds to a regulatory DNA sequence known as the peroxisome proliferator response element. The end result of the interaction between peroxisome proliferators and this system is that genes are switched on, leading to increases in synthesis (induction) of both microsomal and peroxisomal enzymes and possibly hyperplasia. 

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