Heterodimer with RXR

These teceptors, which may have hormones, metabolites, ot dmgs as ligands, bind to specific DNA elements as homodimers or as heterodimers with RXR. Some—orphan receptors—have no known ligand but bind DNA and influence transcription. 

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 two families of receptors differ from each other considerably, 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). 

These retinoid receptors must form dimers before they interact with RAREs. RARs must form heterodimers with RXR.S, whereas RXRs may also form homodimers. It appears that the RAREs for the homodimers differ from those for the heterodimers. This implies that they may activate different sets of genes. RXRs also form hetcrodimers with thyroid hormone receptors and vitamin O receptois. increasing their affinity for DNA. Several enzymes whose expression depends on RXR have been found. The available experimental data provide convincing evidence that these proteins are, in fact, nuclear receptors belonging to the steroid/thyroid hormone superfamily. They mediate important aspects of vitamin A function. The existence of proteins that specifically bind retinoic acid substantiates the implication of retinoic acid as a physiological form of vitamin A. 

Figure 3 The PPAR family and its DNA properties, (a) The murine PPAR subfamily. The DNA and ligand-binding domains are indicated. Numbers represent percentage amino acid identity, (b) The PPARs bind to DR-1-type DNA response elements as heterodimers with RXR. The PPAR/RXR heterodimer can be activated by ligands for either PPAR or RXR. (Reproduced from Kliewer SA, Xu HE, Lambert MH, and Willson TM (2001) Peroxisome proliferator-activated receptors From genes to physiology. Recent Progress in Hormone Research 56 239-265, with permission from The Endocrine Society.)...

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

Steroid and nuclear receptors are differentiated by their mode of DNA binding. GR, PR, AR, and ER all bind as homodimers to inverted-repeat sequences separated by three nucleotides (nnn), although the ER DNA binding domain recognizes a DNA sequence that is shared by the nuclear receptors. Nuclear receptors bind predominantly as heterodimers with RXR to direct-repeat sequences separated by one to five nucleotides. Structural studies have shown that RXR binds to the 50 half-site of the response element, which may be important for ligand-dependent transcriptional regulatory activity of the heterodimeric... 

Analyses of PXR target gene promoters revealed that the receptor can upregulate transcription by binding as a heterodimer with RXR to several different motifs, including DR3, DR4, and ER6 elements (Figure 8.1) . The human CYP3A4... 

Figure 8.1. A model of the transcriptional regulation of CYP3A expression by PXR. The PXR binds as a heterodimer with RXR to response elements in the promoter of CYP3A and other target genes. Binding of ligand to the PXR results in increased CYP3A enzyme activity, which in turn increases the hydroxylation of substrates such as steroids, bile acids, and drugs,...

Figure 8.4. A model of the transcriptional regulation of gene expression by PPARa. The PPARa binds as a heterodimer with RXR to PPREs upstream of target genes. Ligand binding to either the RXR or PPAR activates the transcriptional complex resulting in the induction of numerous genes involved in fatty acid oxidation and metabolism, such as CYP4A.

RARs are believed to interact with retinoic-acid response elements as heterodimers with RXRs However, isolated RAR-retinoic-acid complexes consistently show a molecular weight of45,000 when fractionated by HPSEC, which suggests that it is the monomeric form that is being extracted (2,7) A similar result has been obtained when a nuclear extract is prepared prior to incubation with retinoic acid (3)... 

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