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History of Retinoic Acid Receptors

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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 discovery of retinoic acid receptors arose from research into how vitamins are essential for life. Early studies indicated that Vitamin A was metabolized into an active factor, retinoic acid (RA), which regulates RNA and protein expression in cells. Each step forward in our understanding of retinoic acid in human health was accomplished by the development and application of new technologies. Development cDNA cloning techniques and discovery of nuclear receptors for steroid hormones provided the basis for identification of two classes of retinoic acid receptors, RARs and RXRs, each of which has three isoforms, α, β and ɣ. DNA manipulation and crystallographic studies revealed that the receptors contain discrete functional domains responsible for binding to DNA, ligands and cofactors. Ligand binding was shown to induce conformational changes in the receptors that cause release of corepressors and recruitment of coactivators to create functional complexes that are bound to consensus promoter DNA sequences called retinoic acid response elements (RAREs) and that cause opening of chromatin and transcription of adjacent genes. Homologous recombination technology allowed the development of mice lacking expression of retinoic acid receptors, individually or in various combinations, which demonstrated that the receptors exhibit vital, but redundant, functions in fetal development and in vision, reproduction, and other functions required for maintenance of adult life. More recent advancements in sequencing and proteomic technologies reveal the complexity of retinoic acid receptor involvement in cellular function through regulation of gene expression and kinase activity. Future directions will require systems biology approaches to decipher how these integrated networks affect human stem cells, health, and disease.

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Abbreviations

ChIP:

Chromatin immunoprecipitation

ChIP-seq:

Chromatin immunoprecipitation coupled with deep sequencing

cDNA:

Complementary DNA

CRABP:

Cellular retinoic acid binding protein

CRBP:

Cellular retinol binding protein

DNA:

Deoxyribonucleic acid

DBD:

DNA binding domain

LBD:

Ligand binding domain

NMR:

Nuclear magnetic resonance

RA:

Retinoic acid

RAR:

Retinoic acid receptor

RARE:

Retinoic acid response element

RNA:

Ribonucleic acid

RNA-seq:

High throughput RNA sequencing

RXR:

Retinoic X receptor

VAD:

Vitamin A deficiency

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Acknowledgments

We thank Gabriel R Batres for assistance with the design and preparation of Fig. 1.4.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 975 NE 10th St BRC1374, Oklahoma City, 73165, USA

    Doris M. Benbrook

  2. Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 975 NE 10th St BRC1374, Oklahoma City, 73165, USA

    Doris M. Benbrook

  3. 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

    Pierre Chambon & Cécile Rochette-Egly

  4. Department of Biological Sciences, Tennessee State University, 3500 John A Merritt Blvd, Nashville, 37209, USA

    Mary Ann Asson-Batres

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  1. Doris M. Benbrook
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  3. Cécile Rochette-Egly
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Correspondence to Doris M. Benbrook .

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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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Benbrook, D.M., Chambon, P., Rochette-Egly, C., Asson-Batres, M.A. (2014). History of Retinoic Acid Receptors. 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_1

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