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 SOX9
Homo sapiens
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Overview

Retinoic acid receptors (RARs) are members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. Three RAR family members exist, alpha, beta and gamma, each gene being expressed as several isomers that vary in their N-terminus. Of note, retinoic acid can also modulate the transcriptional activity of other members of the nuclear receptor superfamily, such as PPARbeta/delta, RORbeta and COUP-TFII.[1][2][3]

RARs share the common nuclear receptor organization in several regions of homology, corresponding to different functional domains.[4] The N-terminal A/B region contains the AF-1 transactivation domain, which functions independently of ligand binding. The DNA binding domain, located in region C, is composed of two C4-type zinc fingers and its structure is characteristic of the nuclear receptor superfamily. Finally, the D/E/F regions contain the ligand-binding domain and a second transactivation domain, AF-2, which functions in a ligand-dependent fashion. The structure of ligand binding domain is also typical of the nuclear receptor superfamily, and is formed by a sandwich of 12 alpha helices. The RAR ligand binding domains all bind the all-trans and 9-cis isomers of retinoic acid, but divergence in the ligand-contacting residues has been exploited for the developement of RAR-specific ligands. Ligand binding stabilizes a conformation of the ligand binding domain that allows recruitment of co-activators, often through insertion of an alpha-helical LXXLL coactivator motif into a pocket formed by residues of helices 3, 4 and 12 in the ligand binding domain. The integrity of the C-terminal helix H12, whose positioning differs markedly in the apo- and holo-forms for RARs, was shown to be crucial for induction of F9 cell differentiation by retinoids.[5]

RARs bind DNA as heterodimers with members of another family of NRs, the retinoid X receptors (RXRs), which also include three genes expressed as different isoforms.[6][7][8] RAR/RXR heterodimers bind specific retinoic acid response elements (RAREs), usually composed of two or more repeats of the motif PuG(G/T)TCA arranged as direct repeats but also inverted or everted repeats.[9] In the absence of the ligand retinoic acid (RA), the RAR/RXR heterodimers bound to DNA repress transcription through recruitment of corepressors such as NCoR or SMRT and their associated complexes with histone deacetylase activity. Ligand binding induces a conformational change that induces the dissociation of corepressors and the recruitment of coactivators, including histone acetyl-transferases, histone methyl-transferases, ATP-dependent chromatin remodeling complexes, and of components of the mediator complex and basal transcription machinery.[10][11][12]

RARs play important roles during development and control cell differentiation, proliferation, apoptosis and metabolism through direct DNA binding, but also through tethering to DNA via protein-protein interactions with other transcription factors and through non-genomic mechanisms of action.[12][13][14] Although RARs differ in their patterns of expression, functional redundancy has been observed in mouse knock-out models. Their patterns of DNA binding appear largely similar,[15] although differences in their transcriptional activation function should result in receptor-specific target gene networks.

References
  1. Shaw N et al. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J. Biol. Chem., 278(43):41589-92. (PMID 12963727)
  2. Stehlin-Gaon C et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol., 10(10):820-5. (PMID 12958591)
  3. Kruse SW et al. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol., 6(9):e227. (PMID 18798693)
  4. Germain P et al. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol. Rev., 58(4):712-25. (PMID 17132850)
  5. Plassat J et al. The conserved amphipatic alpha-helical core motif of RARgamma and RARalpha activating domains is indispensable for RA-induced differentiation of F9 cells. J. Cell. Sci., 113 ( Pt 16):2887-95. (PMID 10910773)
  6. Leid M et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell, 68(2):377-95. (PMID 1310259)
  7. Kliewer SA et al. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature, 355(6359):446-9. (PMID 1310351)
  8. Mangelsdorf DJ et al. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev., 6(3):329-44. (PMID 1312497)
  1. Claessens F and Gewirth DT. DNA recognition by nuclear receptors. Essays Biochem., 40:59-72. (PMID 15242339)
  2. Chawla A et al. Nuclear receptors and lipid physiology: opening the X-files. Science, 294(5548):1866-70. (PMID 11729302)
  3. McKenna NJ and O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell, 108(4):465-74. (PMID 11909518)
  4. Rochette-Egly C and Germain P. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). , 7:e005. (PMID 19471584)
  5. Balmer JE and Blomhoff R. Gene expression regulation by retinoic acid. J. Lipid Res., 43(11):1773-808. (PMID 12401878)
  6. Balmer JE and Blomhoff R. A robust characterization of retinoic acid response elements based on a comparison of sites in three species. J. Steroid Biochem. Mol. Biol., 96(5):347-54. (PMID 16081280)
  7. Hua S et al. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell, 137(7):1259-71. (PMID 19563758)
Figures
FIGURE 1 Domain structure of RARs.
Nuclear hormone receptors, including the RARs, share a similar structural architecture composed of four major functional domains: the N-terminal domain (A/B region), which contains a transcriptional activation function, the DNA-binding domain (C region), a hinge region (D region), and the ligand-binding domain (D/E/F region). Regions C and E are the most conserved within the RAR family, but differences in the ligand binding domain can be exploited for design of receptor-specific ligands. Isoforms differ in region A, resulting in different transcriptional activation properties.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.