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Retinoic acid (RA) is a morphogen derived from Retinol (vitamin A) through oxidative reactions mediated by retinol dehydrogenase and retinal dehydrogenase (Ref.1 and 2). Two isomers of RA act as ligands for retinoid signaling: all-trans-RA (atRA) and 9-cis-RA (9cRA). RA exerts its effects through two classes of nuclear receptors: the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) that bind either atRA) or 9cRA. There are three RAR isotypes (a,b, and g
) and three RXR isotypes (a, b, and g
) encoded by distinct genes (Ref.3). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding (Ref. 4).
Retinoid receptors exhibit a modular structure composed of 6 conserved regions designated A–F. The highly conserved C region harbors the DBD which confers sequence specific DNA recognition. Region E corresponds to the LBD. It contains the ligand-binding pocket, the main dimerization domain and the ligand-dependent transactivation function (AF-2). The N-terminal A/B region harbors a ligand-independent transcriptional activation function (AF-1). In the absence of ligand, retinoid receptors bind as asymetric, oriented RAR/RXR heterodimers to specific DNA sequences or RA response elements (RAREs) composed typically of two direct repeats of a core hexameric motif, PuG(G/T)TCA. The classical RARE is a 5-bp-spaced direct repeat, but may also bind to direct repeats separated by 1 bp (DR1) or 2 bp (DR2) (Ref.5).
The ligand-induced conformational changes in the receptors cause the dissociation of corepressors and the coordinated and/or combinatorial recruitment of coactivators. Major receptors coactivators identified include SRC-1, TIF-2, pCIP
, p300/CBP and CARM-1
.Coactivators dissociate, subsequent to their acetylation which decreases their ability to interact with the receptors, or leads to their degradation by the proteasome. The retinoid receptors then recruit the transcription machinery via their association with the so called SMCC-mediator complex. The mediator expedites entry of the transcriptional machinery to the promoter through its interaction with the RNA Pol II
holoenzyme, involving six GTFs
(Ref.5 and 6).
The transcriptional activity of retinoid receptors is also regulated by the ubiquitin–proteasome pathway. One main role of the ubiquitin–proteasome system is to degrade transcriptional activators. In this process, following a signal, the substrate protein is multi-ubiquitylated at a lysine group and then targeted for destruction by the 26Sproteasome. This process involves the ubiquitylation of RARs and the recruitment of the proteasome at the AF-2 domain through SUG-1. The ubiquitin–proteasome machineries may also control the functionality of RARg/RXR heterodimers through helping the recruitment of the transcription machinery. Such a dual role may regulate the dynamic assembly/disassembly of retinoid receptors to the promoter of the target genes (Ref.5 and 7).