TABLE 3

Rev-erbα

Receptor nomenclature NR1D1
Receptor code 4.10.1:OR:1:D1
Other names EAR1, EAR1 A, Rev-erbAα
Molecular information Hs: 614aa, P20393, chr. 17q2113
Rn: 614aa, Q63503, chr. 10q314
Mm: 615aa, Q3UJJ1, chr. 11 D5
DNA binding
   Structure Monomer, homodimer
   HRE core sequence A/T A A/T N T PuGGTCA (DR-2, half-site)
Partners Rev-erbα (physical, functional): DNA binding6
Agonists Homology modeling of the LBD of the NR1D subgroup suggests that the pocket is occupied by bulky side chains and cannot accommodate a classic ligand7
Antagonists
Coactivators NCOA58
Corepressors NCOR1, C1d, HDAC3, NCOA5811
Biologically important isoforms Rev-erbα 2 {Hs, Mm, Rn}: encoded by an mRNA transcribed from an alternative promoter; lacks the first 114aa in the N-terminal domain of Rev-erbα12
Tissue distribution Developmental: heart, eyes, brain (Purkinje cells of the cerebellum, olfactory granule cells, cerebral cortex, hippocampus); adult: skeletal muscle, brown fat, liver, heart, brain, pituitary, kidney, testis, lung, hypothalamus {Hs, Mm} [Northern blot, Q-PCR, in situ hybridization, Western blot, immunohistology]2,3, 1318
Functional assays
Main target genes Repressed: Rev-erbα {Hs, Mm, Rn},6 ApoA1 {Rn},19 ApoCIII {Hs, Mm, Rn},20,21 Bmal1 {Hs, Mm, Rn}12,18
Mutant phenotype Knockout mice exhibit abnormalities in the cerebellum after 2 weeks of life, such as alterations in the development of Purkinje cells, a delay in the proliferation and migration of granule cells, and an increase in apoptosis of neurons in the internal granule cell layer {Mm} [knockout]13; knockout mice have also been shown to exhibit defects in their circadian rhythm {Mm} [knockout]17
Human disease
  • aa, amino acids; chr., chromosome; HRE, hormone response element; Q-PCR, quantitative polymerase chain reaction

  • 1. Miyajima N, Kadowaki Y, Fukushige S, Shimizu S, Semba K, Yamanashi Y, Matsubara K, Toyoshima K, and Yamamoto T (1988) Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res 16: 11057-11074

  • 2. Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, and Yamamoto T (1989) Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 57: 31-39

  • 3. Lazar MA, Jones KE, and Chin WW (1990) Isolation of a cDNA encoding human Rev-ErbA α : transcription from the noncoding DNA strand of a thyroid hormone receptor gene results in a related protein that does not bind thyroid hormone. DNA Cell Biol 9: 77-83

  • 4. Lazar MA, Hodin RA, Darling DS, and Chin WW (1989) A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA α transcriptional unit. Mol Cell Biol 9: 1128-1136

  • 5. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, et al. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA 99: 16899-16903

  • 6. Adelmant G, Begue A, Stehelin D, and Laudet V (1996) A functional Rev-erb α responsive element located in the human Rev-erb α promoter mediates a repressing activity. Proc Natl Acad Sci USA 93: 3553-3558

  • 7. Renaud JP, Harris JM, Downes M, Burke LJ, and Muscat GE (2000) Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. Mol Endocrinol 14: 700-717

  • 8. Sauve F, McBroom LD, Gallant J, Moraitis AN, Labrie F, and Giguere V (2001) CIA, a novel estrogen receptor coactivator with a bifunctional nuclear receptor interacting determinant. Mol Cell Biol 21: 343-353

  • 9. Downes M, Burke LJ, Bailey PJ, and Muscat GE (1996) Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA α and RVR: physical association is dependent on the E region of the orphan receptors. Nucleic Acids Res 24: 4379-4386

  • 10. Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, and Lazar MA (1997) Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc Natl Acad Sci USA 94: 14400-14405

  • 11. Yin L and Lazar MA (2005) The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol Endocrinol 19: 1452-1459

  • 12. Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, and Laudet V (2004) The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker. J Mol Endocrinol 33: 585-608

  • 13. Hastings ML, Milcarek C, Martincic K, Peterson ML, and Munroe SH (1997) Expression of the thyroid hormone receptor gene, erbAα, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res 25: 4296-4300

  • 14. Chomez P, Neveu I, Mansen A, Kiesler E, Larsson L, Vennstrom B, and Arenas E (2000) Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbAα orphan receptor. Development 127: 1489-1498

  • 15. Kainu T, Enmark E, Gustafsson JA, and Pelto-Huikko MP (1996) Localization of the Rev-ErbA orphan receptors in the brain. Brain Res 743: 315-319

  • 16. Chawla A, and Lazar MA (1993) Induction of Rev-ErbAα, an orphan receptor encoded on the opposite strand of the α-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem 268: 16265-16269

  • 17. Downes M, Carozzi AJ, and Muscat GE (1995) Constitutive expression of the orphan receptor, Rev-erbAα, inhibits muscle differentiation and abrogates the expression of the myoD gene family. Mol Endocrinol 9: 1666-1678

  • 18. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, and Schibler U (2002) The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251-260

  • 19. Vu-Dac N, Chopin-Delannoy S, Gervois P, Bonnelye E, Martin G, Fruchart JC, Laudet V, and Staels B (1998) The nuclear receptors peroxisome proliferator-activated receptor α and Rev-erbα mediate the species-specific regulation of apolipoprotein A-I expression by fibrates. J Biol Chem 273: 25713-25720

  • 20. Coste H, and Rodriguez JC (2002) Orphan nuclear hormone receptor Rev-erbα regulates the human apolipoprotein CIII promoter. J Biol Chem 277: 27120-27129

  • 21. Raspe E, Duez H, Mansen A, Fontaine C, Fievet C, Fruchart JC, Vennstrom B, and Staels B (2002) Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription. J Lipid Res 43: 2172-2179