RXR heterodimer

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

Peroxisome Proliferator-Activated Receptors. Figure 2 Binding of PPAR RXR heterodimers to DR1 PPRE-responsive elements. Abbreviations DR1, a direct repeat organization of the A/GGGTCA hexamer half-site separated by a single nucleotide spacer. 

Fig. 4.6. HRE structure of the RXR heterodimer. Shown is the consensus sequence of the HREs of the RXR heterodimers (see Fig. 4.7) and the different possible arrangements of the hexameric half-site sequences. The hexamers can be arranged palindromically as inverted repeats (a), as everted repeats (b), or as direct repeats (c). n indicates the number of base pairs that lie between the two hexamers. RXR receptor for 9-ds retinoic acid RAR receptor for all-trans retinoic acid T3R receptor for the T3 hormon PPAR peroxisome prohferator-activated receptor VDR receptor for vitamin D3.

Ligands of the RXR-heterodimer group and the orphan receptors are chemically more diverse than the ligands of the steroid family. Representative hgands of this group are the retinoids all-trans retinoic acid, 9-cis retinoic acid, the T3 hormone and vitamin D3 (fig. 4.1). 

Fig. 4.11. Principle of signal transduction by RXR heterodimers. The activated hormone can be made available to the RXR heterodimer in three different ways, a) The hormone (e.g. T3 hormone) is synthesized in endocrinal tissue and reaches the DNA-bound RXR-T3R heterodimer in the nucleus via passive transport, b) The active hormone is formed in the cytosol from an inactive apo-hormone (as for, e.g. 9-ds-retinoic add), c) The hormone is synthesized intracellularly. In aU three cases, the binding of the hormone-RXR-heterodimeric complex is the signal that induces transcription activation of the downstream genes. After Mangelsdorf and Evans, 1995.

The HREs and RXR-heterodimers are usually composed of two identical or nearly identical copies of the hexamer sequence AGGTCA in direct repeat. The apparently simple structure of the HREs leads to the question of how the receptors of this class can distinguish between the various HREs. Studies with artificial HRE constructs, as well as of naturally occurring HREs, indicate a complicated cooperative effect between HRE structure on the one hand and homo- or heterodimer formation of the receptors on the other hand. 

In the case of the T3R and RAR specific repressor proteins have been identified which bind to the receptor and mediate an inhibition of transcription (Hoerlein et al, 1995). The repressor proteins are also termed co-repressors Among the repressors are found proteins with histone deacetylase activity (see 1.4.6). The RXR heterodimers possibly stabilize the repressed state of chromatin by recruiting a histone deacetylase to the chromatin. 

Figure 9.10 Illustration depicting DNA elements found in CYP3A genes and the activation of the human pregnane X receptor (PXR) by ligand (RIF) and subsequent transcriptional activation of CYP3A4 gene by the PXR/RXR heterodimer. dNR-1-3, nuclear receptors 1, 2, and 3, respectively PXR, pregnane X receptor RXR, retinoid X receptor RIF, rifampicin SRC-1, steroid receptor co-activator XREM, xenobiotic responsive enhancer module.

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). 

Matt N, Ghyselinck NB, Wendling O, Chambon P, Mark M (2003) Retinoic acid-induced developmental defects are mediated by RARb/RXR heterodimers in the pharyngeal endoderm. Development, 130 2083-2093. 

Figure 9.10. Regulation of target genes by PPAR RXR heterodimers. Fatty acids serve as transcriptional inducers and substrates of enzymes involved in lipid homeostasis. (From Handschin, C., and Meyer, U. A. Induction of drug metabolism The role of nuclear receptors. Pharmacol. Rev. 55 649-673, 2003.)...

CRABP (1) and CRABP (11) function to transport retinoic acid into the nucleus for binding to retinoid receptors. CRABP(ll), with retinoic acid bound, also interacts directly with the liganded RAR-RXR heterodimer bound to hormone response elements on DNA and enhances the activity of the nuclear receptor (Section2.3.2.1 Delvaetal., 1999). 

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). 

The multipUcity of possible combinations of homodimers and heterodimers of RAR and RXR subtypes, and the various possible RXR heterodimers with other receptors, permits a wide variety of active retinoid receptor complexes that bind to different response elements on DNA. Unlike most hormone response elements on DNA, which are palindromic and bind a symmetrical receptor homodimer, the most common type of retinoid response element is a direct repeat purine-G-(G or T)-T-C-A-(Xn)-purine-G-(G or T)-T-C-A, in which the spacer (Xn) is commonly 5 base pairs, but may be 1 or 2. There are also more complex retinoid response elements, including palindromic and inverted palindromic repeats, as well as hexameric motifs with variable spacing. This means that a wide variety of different genes may be regulated differendy in response to retinoids. 

The vitamin D receptor- RXR heterodimer binds in 5 RXR-VDR3 polarity to a direct repeat hormone response element However, the vitamin D receptor also forms heterodimers with the retinoic acid receptor and the thyroid hormone receptor. All three vitamin D receptor dimers can interact with either direct repeat or inverted palindromic hormone response elements. In heterodimers, the vitamin D receptor may be at the 5 -position or 3 -position, resulting in six types of activated vitamin D receptor dimers that can bind to two types of response elements, raising the possibility of multiple signaling pathways (Carlberg, 1996 Carlberg et al., 2001 Yamada et al., 2001b). 

Mangelsdorf D and Evans R (1995) The RXR heterodimers and orphan receptors. Cell 83, 841-50. 

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