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Nuclear and Extra-Nuclear Effects of Retinoid Acid Receptors: How They Are Interconnected

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The Biochemistry of Retinoic Acid Receptors I: Structure, Activation, and Function at the Molecular Level

Part of the book series: Subcellular Biochemistry ((SCBI,volume 70))

Abstract

The nuclear retinoic acid receptors (RAR α, β and γ) and their isoforms are ligand-dependent regulators of transcription, which mediate the effects of all-trans retinoic acid (RA), the active endogenous metabolite of Vitamin A. They heterodimerize with Retinoid X Receptors (RXRs α, β and γ), and regulate the expression of a battery of target genes involved in cell growth and differentiation. During the two last decades, the description of the crystallographic structures of RARs, the characterization of the polymorphic response elements of their target genes, and the identification of the multiprotein complexes involved in their transcriptional activity have provided a wealth of information on their pleiotropic effects. However, the regulatory scenario became even more complicated once it was discovered that RARs are phosphoproteins and that RA can activate kinase signaling cascades via a pool of RARs present in membrane lipid rafts. Now it is known that these RA-activated kinases translocate to the nucleus where they phosphorylate RARs and other retinoid signaling factors. The phosphorylation state of the RARs dictates whether the transcriptional programs which are known to be induced by RA are facilitated and/or switched on. Thus, kinase signaling pathways appear to be crucial for fine-tuning the appropriate physiological activity of RARs.

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Abbreviations

CAK:

Cyclin-dependent kinase (CDK)-activating kinase

ChIP:

Chromatin immunoprecipitation

ChIP-seq:

ChIP coupled with deep sequencing

CRABP:

Cellular retinoic acid binding protein

DBD:

DNA binding domain

DR:

Direct repeat

Erks:

Extracellular-signal-regulated kinases

ES cells:

Embryonic stem cells

FABP:

Fatty acid binding protein

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HMT:

Histone methyl transferase

iLBP:

Intracellular lipid binding protein

IR:

Inverted repeat

LBD:

Ligand binding domain

LBP:

Ligand binding pocket

MAPK:

Mitogen activated protein kinase

MSK:

Mitogen-and stress-activated protein kinase

N-CoR:

Nuclear receptor corepressor

NMR:

Nuclear magnetic resonance

NTD:

N-terminal domain

PcG:

Polycomb group proteins

PI3K:

Phosphoinositide 3-kinase

Pin1:

Protein interacting with NIMA (never in mitosis A)

PPAR:

Peroxysome proliferator activated receptor

PRM:

Proline rich motif

RA:

Retinoic acid

RAR:

Retinoic acid receptor

RARE:

Retinoic acid response element

RNA-seq:

high throughput qPCR sequencing

RXR:

Retinoid X receptor

SAXS:

Small angle X-ray

SH3:

Src-homology-3

SRC:

Steroid receptor coactivator

SMRT:

Silencing mediator of retinoic acid receptor and thyroid hormone receptor

TBL1:

Transducin beta like

TBLR1:

TBL1-related protein 1

WW:

Tryptophan-tryptophan

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Acknowledgments

Funds from the Agence Nationale pour la Recherche (ANR-05-BLAN-0390-02 and ANR-09-BLAN-0297-01), the Foundation pour la Recherche Medicale (FRM, DEQ20090515423), the Institut National du Cancer (INCa-PLO7-96099 and PL09-194) and the Association pour la Recherche sur le Cancer (ARC 3169, ARC SL220110603474) supported this work. This study was also supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the ANR under the frame programme Investissements d'Avenir labelled ANR-10-IDEX-0002-02. INCA supported ZA while FRM and the lady TATA Memorial Trust supported AP.

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  1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U964, CNRS, UMR7104, Université de Strasbourg, 1 rue Laurent Fries, BP 10142, 67404, Illkirch Cedex, France

    Aleksandr Piskunov, Ziad Al Tanoury & Cécile Rochette-Egly

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  1. Aleksandr Piskunov
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Correspondence to Cécile Rochette-Egly .

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  1. Department of Biological Sciences, Tennessee State University, Nashville, Tennessee, USA

    Mary Ann Asson-Batres

  2. IGBMC, Illkirch Cedex, France

    Cécile Rochette-Egly

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Piskunov, A., Al Tanoury, Z., Rochette-Egly, C. (2014). Nuclear and Extra-Nuclear Effects of Retinoid Acid Receptors: How They Are Interconnected. In: Asson-Batres, M., Rochette-Egly, C. (eds) The Biochemistry of Retinoic Acid Receptors I: Structure, Activation, and Function at the Molecular Level. Subcellular Biochemistry, vol 70. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9050-5_6

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