Nuclear receptor subfamily 1, group D, member 1
|PDB rendering based on 1a6y.|
|Available structures:, ,|
|RNA expression pattern|
Rev-ErbA alpha also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), is a member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor. In mammals, Rev-erbα is highly expressed in the liver, skeletal muscle, adipose tissue, and the brain, participating in the development and circadian regulation of these tissues.
Gene and protein structure
Rev-erbα is transcribed from the opposite strand of the thyroid receptor α (c-erbAα) gene on chromosome 17, with a 269-nucleotide overlap between the two transcripts. The other mammalian isoform of the receptor, Rev-erbβ is encoded by another gene on chromosome 3. In addition, there is one non-mammalian homolog, the ecdysone-regulated gene E75, which is present in Drosophila and C. elegans. The Rev-erbα gene itself has multiple transcripts. Two promoters govern the expression of the Rev-erbα gene in human and rat, generating two mRNA isoforms. The full-length isoform encodes a 614-amino acid protein, while a second isoform is generated from an internal promoter and produces a protein that is shorter by 106 amino acids. Both Rev-erbα mRNA isoforms contain E-boxes as well as Rev-erbα response elements, which means that they can be regulated in a circadian manner by the BMAL and Rev-erba proteins. In fact, both transcripts exhibit rhythmic expression in serum-synchronized fibroblasts.
The Rev-erbα protein is structurally unique from other nuclear receptors, in that it lacks Helix 12 in its ligand-binding domain, which is usually responsible for forming the ligand binding pocket in other nuclear receptors. In place of the missing H12, Rev-erbα displays a hydrophobic interface that binds the corepressor N-CoR, making it a potent transcriptional repressor. Interestingly, all members of the Rev-erb family bind heme, which may act as a ligand to regulate their transcriptional activity.
Rev-erbα regulates gene transcription by directly binding to target response elements (RevREs), comprised of an A/T-rich flank followed by AGGTCA. Rev-erbα mediates repression by recruiting the corepressor N-CoR, which then activates the histone deacetylase (HDAC) 3. A number of target genes has been identified for Rev-erbα, including the lipoproteins ApoA1 and ApoCIII, hydratase dehydrogenase, the circadian factor BMAL, and the anti-fibrinolytic factor PAI-1. Many of these genes are coordinately regulated by Rev-erbα and the RAR-related orphan receptor RORα, which share the same response elements but exert opposite effects on gene transcription. Crosstalk between Rev-erbα and RORα likely acts to fine-tune of their target physiologic networks, such as circadian rhythms, metabolic homeostasis, and inflammation.
Rev-erbα mRNA is induced during adipogenesis and is highly expressed in adipose tissue. One study reported that overexpression of Rev-erbα may enhance adipogenesis in cultured mouse adipocytes, but the mechanism of this effect remains to be elucidated. Rev-erbα expression is also regulated at the post-translational level: it is phosphorylated on the amino terminus by Glycogen Synthase Kinase (GSK) 3β, which contributes to its protein stability. It has been shown that lithium, which inhibits GSK3β, can de-stabilize Rev-erbα protein and affect its function in the circadian clock. This may partly explain lithium’s therapeutic effect on circadian diseases such as Bipolar Disorder.
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- Lazar MA, Jones KE, Chin WW (1990). "Isolation of a cDNA encoding human Rev-ErbA alpha: 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 (2): 77-83. PMID 1971514.
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- Adelmant G, Bègue A, Stéhelin D, Laudet V (1996). "A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.". Proc. Natl. Acad. Sci. U.S.A. 93 (8): 3553-8. PMID 8622974.
- Downes M, Burke LJ, Bailey PJ, Muscat GE (1997). "Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors.". Nucleic Acids Res. 24 (22): 4379-86. PMID 8948627.
- Burke LJ, Downes M, Laudet V, Muscat GE (1998). "Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha.". Mol. Endocrinol. 12 (2): 248-62. PMID 9482666.
- Zhao Q, Khorasanizadeh S, Miyoshi Y, et al. (1998). "Structural elements of an orphan nuclear receptor-DNA complex.". Mol. Cell 1 (6): 849-61. PMID 9660968.
- Sierk ML, Zhao Q, Rastinejad F (2001). "DNA deformability as a recognition feature in the reverb response element.". Biochemistry 40 (43): 12833-43. PMID 11669620.
- Coste H, Rodríguez JC (2002). "Orphan nuclear hormone receptor Rev-erbalpha regulates the human apolipoprotein CIII promoter.". J. Biol. Chem. 277 (30): 27120-9. doi:10.1074/jbc.M203421200. PMID 12021280.
- Delerive P, Chin WW, Suen CS (2002). "Identification of Reverb(alpha) as a novel ROR(alpha) target gene.". J. Biol. Chem. 277 (38): 35013-8. doi:10.1074/jbc.M202979200. PMID 12114512.
- Raspè E, Mautino G, Duval C, et al. (2003). "Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha.". J. Biol. Chem. 277 (51): 49275-81. doi:10.1074/jbc.M206215200. PMID 12377782.
- Raspé E, Duez H, Mansén A, et al. (2003). "Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription.". J. Lipid Res. 43 (12): 2172-9. PMID 12454280.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899-903. doi:10.1073/pnas.242603899. PMID 12477932.
- Chopin-Delannoy S, Thénot S, Delaunay F, et al. (2004). "A specific and unusual nuclear localization signal in the DNA binding domain of the Rev-erb orphan receptors.". J. Mol. Endocrinol. 30 (2): 197-211. PMID 12683943.
- Fontaine C, Dubois G, Duguay Y, et al. (2003). "The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation.". J. Biol. Chem. 278 (39): 37672-80. doi:10.1074/jbc.M304664200. PMID 12821652.
- Johnson JM, Castle J, Garrett-Engele P, et al. (2004). "Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.". Science 302 (5653): 2141-4. doi:10.1126/science.1090100. PMID 14684825.
- Migita H, Morser J, Kawai K (2004). "Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells.". FEBS Lett. 561 (1-3): 69-74. doi:10.1016/S0014-5793(04)00118-8. PMID 15013753.
- Cheng H, Khanna H, Oh EC, et al. (2005). "Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors.". Hum. Mol. Genet. 13 (15): 1563-75. doi:10.1093/hmg/ddh173. PMID 15190009.
- Beausoleil SA, Jedrychowski M, Schwartz D, et al. (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins.". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130-5. doi:10.1073/pnas.0404720101. PMID 15302935.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121-7. doi:10.1101/gr.2596504. PMID 15489334.
Transcription factors and intracellular receptors
|(1) Basic domains|
|(2) Zinc finger|
|(4) β-Scaffold factors with|
minor groove contacts
| (0) Other|
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