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      Chronicle of a discovery: the retinoic acid receptor

      Author(s): 1 , 2 , 3
      Publication date (Print):
      Journal: Journal of Molecular Endocrinology
      Publisher: Bioscientifica

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          Abstract

          The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid receptors. This stunning breakthrough triggered a cascade of studies to deconstruct the roles played by the RAR and its natural and synthetic ligands in embryonic development, skin, growth, physiology, vision, and disease as well as providing a template to elucidate the molecular mechanisms by which nuclear receptors regulate gene expression. In this review, written from historic and personal perspectives, we highlight the milestones that led to the discovery of the RAR and the subsequent studies that enriched our knowledge of the molecular mechanisms by which a low-abundant dietary compound could be so essential to the generation and maintenance of life itself.

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          The steroid and thyroid hormone receptor superfamily.

          Ronald Evans (1988)
          Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.
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            Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

            Gilbert S. Omenn, Gary Goodman, Mark Thornquist … (1996)
            Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
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              Nuclear Receptors, RXR, and the Big Bang.

              Ronald Evans, David J. Mangelsdorf (2014)
              Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Vincent Giguère: (View ORCID Profile)
                Ronald M Evans: (View ORCID Profile)
                Journal
                Title: Journal of Molecular Endocrinology
                Publisher: Bioscientifica
                ISSN (Print): 0952-5041
                ISSN (Electronic): 1479-6813
                Publication date Created: November 01 2022
                Publication date (Print): November 01 2022
                Volume: 69
                Issue: 4
                Pages: T1-T11
                Affiliations
                [1 ]Goodman Cancer Institute, McGill University, Montréal, Quebec, Canada
                [2 ]Department of Biochemistry, McGill University, Montréal, Quebec, Canada
                [3 ]The Salk Institute for Biological Studies, La Jolla, California, USA
                Article
                DOI: 10.1530/JME-22-0117
                PubMed ID: 35900848
                SO-VID: 5c8172b4-c501-4bde-9c89-525cea8d2d6d
                Copyright © © 2022
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