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      Nuclear receptor Rev-erbα: a heme receptor that coordinates circadian rhythm and metabolism

      review-article
      , ,
      Nuclear Receptor Signaling
      The Nuclear Receptor Signaling Atlas

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          Abstract

          Nuclear receptor Rev-erbα (NR1D1), previously considered to be an orphan nuclear receptor, is a receptor for heme, which promotes transcriptional repression via recruitment of the NCoR-HDAC3 corepressor complex. Rev-erbα gene regulation is circadian, and Rev-erbα comprises a critical negative limb of the core circadian clock by directly repressing the expression of the positive clock component, Bmal1. Rev-erbα also regulates the metabolic gene pathway, thus serving as a heme sensor for coordination of circadian and metabolic pathways.

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          The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

          Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
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            The genetics of mammalian circadian order and disorder: implications for physiology and disease.

            Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
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              The renaissance of GSK3.

              Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.
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                Author and article information

                Journal
                Nucl Recept Signal
                NURSA
                Nuclear Receptor Signaling
                The Nuclear Receptor Signaling Atlas
                1550-7629
                2010
                16 April 2010
                : 8
                : e001
                Affiliations
                University of Michigan School of Medicine, Ann Arbor, Michigan (L. Y.) and Division of Endocrinology, Diabetes, and Metabolism and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (N. W. and M. A. L.); (L. Y. and N. W. contributed equally to this work)
                Author notes
                []Corresponding author: lazar@ 123456mail.med.upenn.edu
                Article
                10.1621/nrs.08001
                2858265
                20414452
                692a2488-57f1-4998-a273-1b2f8c0a600e
                Copyright © 2010, Yin et al. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited.
                History
                : 31 October 2009
                : 24 February 2010
                Categories
                Perspective

                Molecular biology
                Molecular biology

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