Retinoic acid receptor response elements

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. 

The response elements for glucocorticoids and estrogen receptors contain short palindromic sequences with various three-nucleotide "spacer" sequences in the center as follows.308,314,316-318 Two receptor proteins bind to the palindromic DNA forming a ho-modimeric receptor pair. For the 9-cis retinoic acid receptor RXR-a the response element contains a pair of direct repeats of a 6-base consensus sequence with a two-base pair spacer ... 

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). 

Figure 30-4. Hormone action of 1,25-dihydroxyvitamin D. VDR, vitamin D receptor RXR, retinoic acid receptor VDRE, vitamin D response element.

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). 

A notable feature of retinoic acid nuclear receptors is that their DBDs and LBDs can communicate with each other retinoic acid receptors bound to DNA response elements modulate ligand binding through a kind of feedback mechanism. This allows fine tuning of ligand-dependent transcriptional activity. 

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-... 

Abbreviations used in text AA, arachidonic acid AhR, aryl hydrocarbon receptor Amt, AhR nuclear translocator BR, bilirubin BV, biliverdin CYP1A1, cytochrome P4501A1 DRE, dioxin responsive element FICZ, 6-formylindolo(3,2b)carbazole HAH, halogenated aromatic hydrocarbon I3C, indole 3-carbinol ICZ, indolo-(3,2,-b)-carbazole PAH, polycyclic aromatic hydrocarbon RAR, retinoic acid receptor TCDD, 2,3,7,8-tetrachlorodi benzo-/>-dioxin Trp, tryptophan UGT 01, UDP-glucuronosy 1 transferase 01... 

Thyroid hormone, 1,25-dihydroxy vitamin D, and retinoic acid receptor regulation of transcription. The hormone receptor (HR) is dimerized at site (3) and is bound to DNA at hormone response element site (2). Without the ligand, transcription is inactive due to the interaction of HR with corepressor at site 4. When the ligand (hormone) binds to HR, the bound corepressor dissociates leading to an interaction between the coactivator and HR. These regulatory changes result in increased transcription. 

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