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Research article rars






Nuclear Receptor Resource
The Retinoic Acids Receptors
P.P. Albrecht, J.P. Vanden Heuvel, INDIGO Biosciences Inc., State College PA Retinoic Acid Receptors
1 Overview
Retinoic acid receptors (RAR) are nuclear receptors from ‘Thyroid hormone receptor-like family' that mediate the effects of retinoids (compounds such as Vitamin A, its metabolites, and synthetic analogs). RARs play a role in various biological processes such as vertebrate embryonic morphogenesis, organogenesis, cell growth arrest, differentiation and apoptosis, homeostasis. On a structural level, RARs are similar to other nuclear receptors Ligand$Binding$ +$dimerizaJon$ +$silencing$ $ $ $ and have A to F domains (Figure 1). Domain A/B is termed as AF-1 and functions as a ligand-independent transcriptional activation domain. Domain C is highly conserved between different isoforms and corresponds to DNA-binding domain. Region E contains ligand-binding domain, dimerization domain and a silencing domain. Figure 1. Basic Structure of the retinoic acid receptors Upon ligand binding, the receptor undergoes major structural changes exposing/creating new surfaces for coactivator binding. The function of domain F is not • is essential for growth arrest, visceral endodermal known (McKenna and O'Malley 2002). There are three subtypes of RARs namely RARα • Mutations lead to growth deficiency, male sterility, (NR1B1, also known as RARA), RARβ (NR1B2, also webbed digits, malformations of respiratory system etc.
known as RARB or HAP), and RARγ (NR1B3, also known as RARG). For each subtype several isoforms exist 2. Basic Mechanism of Action
which differ from one another in their N-terminal region (A domain). Two major isoforms exist for RAR RARs heterodimerize with retinoid X receptor (RXR) α (NR2B1), RXRβ (NR2B2) and RXRγ (NR2B3) (see Figure α2), and RARγ (γ1 and γ2) whereas RARβ has four isoforms ( 2). In the absence of an agonist RARs bind to RXR and β1, β2, β3, β4). These isoforms are formed due to differential usage of promoters and alternative splicing. recruit the co-repressor proteins NCoR or SMRT along with factors such as histone deacetylase (HDACs) or DNA α is present in most of the tissues. RARβ is found in brain, liver, kidney, heart, pituitary, colon, uterus, ovary, methyltransferases. Upon availability of an agonist or testis, prostate, adrenal, and eye. RAR ligand, corepressors are released and coactivator complexes γ is highly expressed such as histone acetyltransferases or histone arginine in epidermis. All three RARs play important roles, more methyltransferases are recruited (Tang & Gudas 2011, Glass & Rosenfeld 2011, le Maire, A. et al 2010). Upon activation RAR-RXR heterodimers bind to retinoic acid • is needed for parietal endodermal differentiation response element (RARE) DNA sequences found in • inhibits cell proliferation in breast cancer cell line responsive genes such as CD38, CEBP, Hoxa-1, HNF3 • induces maturation of acute myeloid leukemia cell line β, Stra4 and Stra6 (Perissi and Rosenfeld 2005). RARs also take part in various signaling pathways • Mutations in RARβ show growth retardation, behavioral through posttranslational modifications including defects, congenital defects etc. Additionally many cancers phosphorylation. Kinases (cdks, MAPKs) act on AF-1 have RARβ promoter silenced and as result decreased domain and LBDs of RARs. It is also known that ligand- expression of RARβ.
driven RARs lead to inhibition of AP-1 although the 2012 Jack Vanden Heuvel, PhD. INDIGO Biosciences, Inc.
Reprint  permi*ed  with  the  fol owing  cita4on:  Prajakta  P.  Albrecht  and  John  P.  Vanden  Heuvel,  nrresource.org



Nuclear Receptor Resource
The Retinoic Acids Receptors
P.P. Albrecht, J.P. Vanden Heuvel, INDIGO Biosciences Inc., State College PAmechanism of which remains unknown (Rochette-Egly and Chambon 2001, Chambon 2005) 4. Natural RAR Modulators
Natural retinoids are produced in the body from oxidation
of vitamin A by alcohol and aldehyde dehydrogenases.
The resulting ATRA is a very potent ligand for RARα, β,
and γ subtypes. ATRA can isomerize to form 9CRA which can bind to RARs as well as RXRs and peroxisome proliferator-activated receptors (PPARs). Many synthetic analogs were developed recently which have specific activities for one or more of RAR subtypes such as AM80 which is a selective RARα agonist (Allenby G. et al. 1993, Germain P. et al. 2006). - Allenby, G. et al (1993). Retinoic Acid Receptors and Retinoid X Receptors: Interactions with Endogenous Retinoic Acids. Proc Natl Acad Sci USA 90: 30-4.
- Chambon, P. (2005). The Nuclear Receptor Superfamily: A Personal Retrospect on the First Two Decades. Mol Endocrinol 19: 1418-28.
Figure 2. Regulation of gene expression by RAR. - Germain, P. et al. (2006). International Union of Pharmacology. LX. Retinoic Acid Receptors. Pharmacol Rev 58: 712-25.
- Glass, C.K. and Rosenfeld, M.G. (2000). The 3. RARs as a therapeutic target
Coregulator Exchange in Transcriptional Functions of Acute promyelocytic leukemia is a cancer of blood &
Nuclear Receptors. Genes Dev 14: 121-41.
bone marrow, in which promyelocytes accumulate in - le Maire, A. et al. (2010). A Unique Secondary-Structure blood and result in anemia. The disease is characterized Switch Controls Constitutive Gene Repression by by chromosomal translocation between RAR alpha gene Retinoic Acid Receptor. Nat Struct Mol Biol 17: 801-7.
and promyelocyte leukemia protein resulting in formation - McKenna, N.J. and O'Malley, B.W. (2002). of fusion protein. The fusion protein binds strongly to Combinatorial Control of Gene Expression by Nuclear transcriptional corepressors resulting in RAR alpha gene Receptors and Coregulators. Cell 108: 465-74.
- Perissi, V. and Rosenfeld, M.G. (2005). Controlling silencing. This in-turn results in blockade of Nuclear Receptors: The Circular Logic of Cofactor differentiation of cells. High doses of all-trans retinoic Cycles. Nat Rev Mol Cell Biol 6: 542-54.
acid (ATRA) rescue RARα from the silencing complex - Rochette-Egly, C. and Chambon, P. (2001). F9 resulting in activation of differentiation. Approximately Embryocarcinoma Cells: A Cell Autonomous Model to 72% patients suffering from this disease can be cured Study the Functional Selectivity of RARs and RXRs in upon ATRA treatment.
Retinoid Signaling Histol Histopathol 16: 909-22.
- Tang, X.H. and Gudas, L.J. (2011). Retinoids, Retinoic Dermatological indications-Clinically ATRA, 9-cis
Acid Receptors, and Cancer. Annu Rev Pathol 6: 345-64.
retinoic acid (9CRA), 13-cis-retinoic acid have been used for acne, psoriasis or photoaging. Additionally various synthetic retinoids are used for treatment of stable plaque psoriasis (eg. Tazarotene, adapalene). Cancer-Retinoids can be used as chemopreventive agents
for treatment of preneoplastic diseases such as oral
leukoplakia,
xerodermapigmentosum. 2012 Jack Vanden Heuvel, PhD. INDIGO Biosciences, Inc.
Reprint  permi*ed  with  the  fol owing  cita4on:  Prajakta  P.  Albrecht  and  John  P.  Vanden  Heuvel,  nrresource.org

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