Rev-ErbA alpha

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Nuclear receptor subfamily 1, group D, member 1
Protein NR1D1 PDB 1a6y.png
The DNA binding domain of NR1D1 bound to double stranded DNA.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NR1D1 ; EAR1; THRA1; THRAL; ear-1; hRev
External IDs OMIM602408 MGI2444210 HomoloGene23324 IUPHAR: NR1D1 GeneCards: NR1D1 Gene
RNA expression pattern
PBB GE NR1D1 31637 s at tn.png
PBB GE NR1D1 204760 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 9572 217166
Ensembl ENSG00000126368 ENSMUSG00000020889
UniProt P20393 Q3UV55
RefSeq (mRNA) NM_021724 NM_145434
RefSeq (protein) NP_068370 NP_663409
Location (UCSC) Chr 17:
38.25 – 38.26 Mb
Chr 11:
98.77 – 98.78 Mb
PubMed search [1] [2]

Rev-ErbA alpha also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), is a protein that in humans is encoded by the NR1D1 gene.[2]

Rev-erbα is member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor.[3] 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.[4][5]

Gene and protein structure[edit]

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.[3] 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 (H12) 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.[6] Interestingly, all members of the Rev-erb family bind heme, which may act as a ligand to regulate their transcriptional activity.[7]

Physiologic function[edit]

Rev-erbα regulates gene transcription by directly binding to target response elements (RevREs), and comprises 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 have been identified for Rev-erbα, including the lipoproteins ApoA1 and ApoCIII, hydratase dehydrogenase, the circadian factor BMAL, and the anti-fibrinolytic factor PAI-1.[8] 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 their target physiologic networks, such as circadian rhythms, metabolic homeostasis,[9] and inflammation.[10]

Rev-erbα mRNA is induced during adipogenesis and is highly expressed in adipose tissue.[11] 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.[12] More recently, a study showed that the deletion of Rev-erbα in mice alters glucose and lipid metabolism and leads to obesity.[13]

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.[14] This may partly explain lithium’s therapeutic effect on circadian diseases such as bipolar disorder.

References[edit]

  1. ^ PDB 1a6yZhao Q, Khorasanizadeh S, Miyoshi Y, Lazar MA, Rastinejad F (May 1998). "Structural elements of an orphan nuclear receptor-DNA complex". Mol. Cell 1 (6): 849–61. doi:10.1016/S1097-2765(00)80084-2. PMID 9660968. 
  2. ^ Lazar MA, Jones KE, Chin WW (March 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. doi:10.1089/dna.1990.9.77. PMID 1971514. 
  3. ^ a b Lazar MA, Hodin RA, Cardona G, Chin WW (1990). "Gene expression from the c-erbA α/Rev-ErbA α genomic locus. Potential regulation of alternative splicing by opposite strand transcription". J. Biol. Chem. 265 (22): 12859–63. PMID 2165488. 
  4. ^ Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002). "The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell 110 (2): 251–60. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932. 
  5. ^ Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V (2004). "The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker". J. Mol. Endocrinol. 33 (3): 585–608. doi:10.1677/jme.1.01554. PMID 15591021. 
  6. ^ Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Eon Ryu S (2007). "Structural Insight into the Constitutive Repression Function of the Nuclear Receptor Rev-erbβ". J. Mol. Biol. 373 (3): 735–44. doi:10.1016/j.jmb.2007.08.037. PMID 17870090. 
  7. ^ Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F (December 2007). "Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ". Nat. Struct. Mol. Biol. 14 (12): 1207–13. doi:10.1038/nsmb1344. PMC 2743565. PMID 18037887. 
  8. ^ Wang J, Yin L, Lazar MA (2006). "The orphan nuclear receptor Rev-erb α regulates circadian expression of plasminogen activator inhibitor type 1". J. Biol. Chem. 281 (45): 33842–8. doi:10.1074/jbc.M607873200. PMID 16968709. 
  9. ^ Delezie J, Challet E (2011). "Interactions between metabolism and circadian clocks: reciprocal disturbances.". Ann N Y Acad Sci 1243: 30–46. doi:10.1111/j.1749-6632.2011.06246.x. PMID 22211891. 
  10. ^ Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM (1994). "Cross-talk among ROR α 1 and the Rev-erb family of orphan nuclear receptors". Mol. Endocrinol. 8 (9): 1253–61. doi:10.1210/me.8.9.1253. PMID 7838158. 
  11. ^ Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, Soncin F, Mandrup S, Fruchart JC, Fruchart-Najib J, Staels B (2003). "The orphan nuclear receptor Rev-Erbα 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. 
  12. ^ Chawla A, Lazar MA (1993). "Induction of Rev-ErbA α, an orphan receptor encoded on the opposite strand of the α-thyroid hormone receptor gene, during adipocyte differentiation". J. Biol. Chem. 268 (22): 16265–9. PMID 8344913. 
  13. ^ Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P et al. (2012). "The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism.". FASEB J 26 (8): 3321–35. doi:10.1096/fj.12-208751. PMID 22562834. 
  14. ^ Yin L, Wang J, Klein PS, Lazar MA (2006). "Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock". Science 311 (5763): 1002–5. doi:10.1126/science.1121613. PMID 16484495. 

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