Nuclear retinoic acid (RA) receptors (RARs) consist of three subtypes, α (NR1B1), β (NR1B2) and γ (NR1B3) encoded by separate genes [Germain et al., 2006a
; Germain et al., 2006c
], which function as ligand-dependent transcriptional regulators heterodimerized with retinoid X receptors (RXRs). For each subtype, there are at least 2 isoforms, which are generated by differential promoter usage and alternative splicing and differ only in their N-terminal regions. Activation of RARs by cognate ligands triggers transcriptional events leading to the activation or repression of subsets of target genes involved in cellular differentiation, proliferation and apoptosis ([Bour et al., 2006
], and references therein).
The compounds that bind RARs and modulate their activity are referred to as retinoids. This generic term covers molecules that include natural vitamin A (retinol) metabolites and active synthetic analogs. Retinoids are hydrophobic, lipid-soluble, and of small size, so that they can easily cross the lipid bi-layer of cell membranes.
Natural retinoids, exemplified by all-trans
RA, are produced in vivo
from the oxidation of vitamin A [Chambon, 2005
; Sporn et al., 1994
] (). An isomerization product of RA, 9-cis
RA, also binds RARs with high affinity, but whether this compound is a natural bioactive retinoid remains controversial [Germain et al., 2006b
Chemical structure, transcriptional activity, and selectivity of main retinoids.
Beyond the natural compounds, major research efforts in retinoid chemistry have been directed towards the identification of potent synthetic molecules and led to the generation of several classes of compounds with a panel of activities ranging from agonists to antagonists, selective or not to RAR subtypes [de Lera et al., 2007
Note that for (B) and (D) in , a given ligand may be considered as selective for a certain RAR subtype when it exhibits an affinity difference greater than 100-fold between its primary target and other receptors (see the recommended usage of terms in the field of nuclear receptors [Germain et al., 2006c
RARs have a well-defined domain organization and structure, consisting mainly of a central DNA-binding domain (DBD) linked to a C-terminal ligand-binding domain (LBD) (). In the past 20 years, it has been established that the basic mechanism for transcriptional regulation by RARs relies on DNA binding to specific sequence elements located in the promoters of target genes and on ligand-induced conformational changes in the LBD that direct the dissociation/association of several coregulator complexes [Chambon, 1996
; Germain et al., 2003
; Laudet and Gronemeyer, 2001
; Lefebvre et al., 2005
]. The description of the crystallographic structures of these domains and the characterization of the multiprotein complexes that specify the transcriptional activity of RARs provided a wealth of information on how these receptors regulate transcription. However, recent years have witnessed the importance of the ubiquitin-proteasome system and that of the N-terminal domain (NTD), which also interacts with specific coregulators, despite its native disordered structure [Bour et al., 2007
]. Moreover, according to recent studies, RARs are involved in other nongenomic biological activities such as the activation of translation and of kinase cascades. These kinases target RARs and their coregulators, adding more complexity to the understanding of RAR-mediated transcription. In this review we will focus, in addition to the basic scenario (DNA and ligand binding, dynamics of coregulator exchanges at the LBD), on recent advances in the nongenomic effects of RA, and on how phosphorylation cascades, the NTD and the ubiquitin-proteasome system cooperate for fine-tuning RAR activity.
Schematic representation of the RAR proteins with the functional domains and the main phosphorylation sites.