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Review
. 2009 May 8:7:e005.
doi: 10.1621/nrs.07005.

Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs)

Cécile Rochette-Egly  1 , Pierre Germain
Affiliations
Review

Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs)

Cécile Rochette-Egly et al. Nucl Recept Signal. .

Abstract

Nuclear retinoic acid receptors (RARs) are transcriptional regulators controlling the expression of specific subsets of genes in a ligand-dependent manner. The basic mechanism for switching on transcription of cognate target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes, the assembly of which is directed by the C-terminal ligand-binding domain of RARs. In addition to this scenario, new roles for the N-terminal domain and the ubiquitin-proteasome system recently emerged. Moreover, the functions of RARs are not limited to the regulation of cognate target genes, as they can transrepress other gene pathways. Finally, RARs are also involved in nongenomic biological activities such as the activation of translation and of kinase cascades. Here we will review these mechanisms, focusing on how kinase signaling and the proteasome pathway cooperate to influence the dynamics of RAR transcriptional activity.

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Figures

Figure 1
Figure 1. Chemical structure, transcriptional activity, and selectivity of main retinoids.
See text for details.
Figure 2
Figure 2. Schematic representation of the RAR proteins with the functional domains and the main phosphorylation sites.
RARs have a modular structure composed of six conserved regions designated A to F. The C region contains the DBD. The E region contains several domains, the LBD, the AF-2 domain, the cyclin H binding domain and the dimerisation domain. It also contains a phosphorylation site for several kinases (PKA and MSK1). The N-terminal domain (NTD) corresponds to regions A and B and contains a proline-rich motif with phosphorylation sites for Cdks and MAPKs.
Figure 3
Figure 3. Crosstalk between kinase cascades and genomic pathways induced by RA.
In response to RA, PKCδ, p38MAPK and the downstream protein kinase MSK1 are activated through rapid nongenomic effects that occur in the cytosol or at the membrane. MSK1 phosphorylates RARα at S369 located in the LBD, subsequently allowing the docking of cyclin H within TFIIH and the formation of a RARα/TFIIH complex. Then the cdk7 subunit of TFIIH phosphorylates the NTD of RARα at S77. Finally, RARα phosphorylated and associated with TFIIH is recruited to response elements located in the promoter of target genes. P38MAPK, MSK1 and PKCδ also phosphorylate corepressors, coactivators and histones. All these phosphorylation processes cooperate to coordinate and fine-tune the dynamic exchanges between RARs, coactivators, corepressors and the promoters of target genes
Figure 4
Figure 4. Recapitulation of the different signaling pathways involved in RAR phosphorylation.
The pathways that are induced by RA are in red. The consequences (positive or negative) of RAR phosphorylation on RA target genes transcription are also indicated. (1) Gianni et al., 2002a. (2) Bour et al., 2005b. (3) Sun et al., 2007. (4) Delmotte et al., 1999. (5) Srinivas et al., 2005. (6) Bruck et al., 2009. (7) Rochette-Egly et al., 1997. (8) Poon and Chen, 2008.
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