Retinoid receptors dimerization

Fig. 16.14. Activity of the thyroid hormone receptor-retinoid receptor dimer (TR-RXR) in the presence and absence of thyroid hormone (T3). Abhrev HAC, histone acetylase HDAC, histone deacetylase.

As shown in Figure 11.5, there are two families of nuclear retinoid receptors the retinoic acid receptors (RAR) bind A -trans-Ktmoic acid or 9- r-retinoic acid and the retinoid X receptors (RXR) bind 9- r-retinoic acid. Retinoic acid is involved in the regulation of a wide variety of genes there are three types of activated retinoid receptor dimers, which bind to different response elements on DNA ... 

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). 

Structural information about retinoid receptors is available. This information has contributed greatly to the elucidation of the structural basis of ligand binding, dimerization, and recognition of DNA response elonents, for retinoid receptors in particular, and... 

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. 

Retinoic X receptors (RXR, a, (3 and " (), also termed rexinoid receptors, are usually classified among orphan receptors, but belong to the thyroid/retinoid family. RXR is an obligatory partner dimerizing with other thyroid/retinoid receptors. RXR selectively bind the 9-cis isomer of retinoic acid, whereas RAR bind aU-tran retinoic acid as well as its 9-cis isomer. RXR selective agonists are termed rexi-noids, like bexarotene used as an antineoplastic in the treatment of cutaneous T-cell lymphoma and the cutaneous lesions of T-cell lymphomas and Kaposi s sarcoma. 

Activator protein-1 (AP-1) is an important transcription factor that figures in the inflammation response. AP-1 is a dimeric complex of the protooncoproteins jun and fos that is induced by growth factors, cytokines, tumor promoters, and sunlight [39]. Activation of AP-1 increases the transcription of cytokines, such as interleukin-2, and certain matrix metalloproteinases [40]. In the presence of t-RA, RARs can inhibit the actions of AP-1. Reciprocally, elevated expression of either the jun or fos components of AP-1 can prevent activation of RAREs by RARs. This repression of gene transcription, called transrepression, is a well-known mechanism for crosstalk between retinoid receptors and AP-1 [41-43]. The molecular mechanism of transrepression described for in vitro systems is dependent on the presence of t-RA and is believed to involve direct or indirect protein-protein interactions between retinoid receptors and AP-1 components (jun and fos), and/or competition between retinoid receptors and AP-1 for a common factor (or factors) required for their activities [42, 43]. However, this phenomenon studied in the context of photoaging of human skin in vivo has revealed a novel mechanism. 

The retinoid receptors function as dimers. Thus, the RAR subtypes heterodimerize with the RXR subtypes. The RXRs also can homodimerize or heterodimerize with the vitamin D, thyroid hormone, and the orphan receptors. The receptor dimers act either directly or indirectly to regulate gene function. The dimers bind directly to retinoid response elements (RAREs and RXREs). These response elements (REs) are specific sequences in the promoter regions of retinoid-responsive genes, which typically consist of two conserved sequences of six nucleotide bases that are separated by discrete numbers of bases. For example, RXR-RAR dimers bind to RAREs which are direct repeats of AGGTCA separated by five (synthetic DR-5 sequence) or two (synthetic DR-2) nucleotides or are palindromic, inverted, or more complex in structure [6]. 

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

Martin, G., Poirier, H., Hennuyer, N., Crombie, D., Fruchart, J. C., Heyman, R. A., Besnard, P., and Auwerx, J. (2000). Induction Of The Fatty Acid Transport Protein 1 and Acyl-Coa Synthase Genes by Dimer-Selective Rexinoids Suggests That the Peroxisome Proliferator-Activated Receptor-Retinoid X Receptor Heterodimer is Their Molecular Target./ Bid. Chem. 275, 12612-12618. 

The vitamin D receptor acts mainly as a heterodimer with the retinoid X receptor (RXR Section 2.3.2.1). Binding of calcitriol induces a conformational change in the receptor protein, permitting dimerization with occupied or unoccupied RXR, followed by phosphorylation to activate binding to the vitamin D response element on DNA (DeLuca and Zierold, 1998). Abnormally high concentrations of 9-cis-retinoic acid result in sequestration of RXR as the homodimers, meaning that it is unavailable to form heterodimers with the vitamin D receptor (or other receptors) excessive vitamin A can therefore antagonize the nuclear actions of vitamin D (Haussler et al., 1995 Rohde et al., 1999). 

Poly(ADP-ribose) polymerase may also have a role in regulating the activity of nuclear-acting hormone receptors it hinds directly to retinoid X receptors (Section 2.3.2.1) andinhihits the transcriptional activity of retinoid X receptor-thyroid hormone dimers, it also acts as a transcription factor in pancreatic /S-islet cells (Miyamoto et al., 1999). 

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