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'''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]].<ref name="pmid1971514">{{cite journal | vauthors = Lazar MA, Jones KE, Chin WW | title = 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 | journal = DNA and Cell Biology | volume = 9 | issue = 2 | pages = 77–83 | date = Mar 1990 | pmid = 1971514 | doi = 10.1089/dna.1990.9.77 }}</ref>
'''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]].<ref name="pmid1971514">{{cite journal | vauthors = Lazar MA, Jones KE, Chin WW | title = 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 | journal = DNA and Cell Biology | volume = 9 | issue = 2 | pages = 77–83 | date = Mar 1990 | pmid = 1971514 | doi = 10.1089/dna.1990.9.77 }}</ref>


Rev-erbα is a member of the [[Rev-ErbA]] family of [[nuclear receptor]]s and is a [[transcription (genetics)|transcriptional]] repressor.<ref name="pmid2165488">{{cite journal | vauthors = Lazar MA, Hodin RA, Cardona G, Chin WW | title = Gene expression from the c-erbA alpha/Rev-ErbA alpha genomic locus. Potential regulation of alternative splicing by opposite strand transcription | journal = The Journal of Biological Chemistry | volume = 265 | issue = 22 | pages = 12859–63 | date = Aug 1990 | pmid = 2165488 | doi =  | url = http://www.jbc.org/cgi/content/abstract/265/22/12859 }}</ref> In mammals, Rev-erbα is highly expressed in the liver, skeletal muscle, adipose tissue, and the brain, participating in the [[developmental biology|development]] and [[circadian rhythm|circadian]] regulation of these tissues.<ref name="pmid12150932">{{cite journal | vauthors = Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U | title = The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator | journal = Cell | volume = 110 | issue = 2 | pages = 251–60 | date = Jul 2002 | pmid = 12150932 | doi = 10.1016/S0092-8674(02)00825-5 }}</ref><ref name="pmid15591021">{{cite journal | vauthors = Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V | title = The orphan receptor Rev-erbalpha gene is a target of the circadian clock pacemaker | journal = Journal of Molecular Endocrinology | volume = 33 | issue = 3 | pages = 585–608 | date = Dec 2004 | pmid = 15591021 | doi = 10.1677/jme.1.01554 }}</ref>
Rev-erbα is a member of the [[Rev-ErbA]] family of [[nuclear receptor]]s and is a [[transcription (genetics)|transcriptional]] repressor.<ref name="pmid2165488">{{cite journal | vauthors = Lazar MA, Hodin RA, Cardona G, Chin WW | title = Gene expression from the c-erbA alpha/Rev-ErbA alpha genomic locus. Potential regulation of alternative splicing by opposite strand transcription | journal = The Journal of Biological Chemistry | volume = 265 | issue = 22 | pages = 12859–63 | date = Aug 1990 | pmid = 2165488 | doi =  | url = http://www.jbc.org/cgi/content/abstract/265/22/12859 }}</ref> In mammals, Rev-erbα is highly expressed in the liver, skeletal muscle, adipose tissue, and the brain, participating in the [[developmental biology|development]] and [[circadian rhythm|circadian]] regulation of these tissues.<ref name="pmid12150932">{{cite journal | vauthors = Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U | title = The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator | journal = Cell | volume = 110 | issue = 2 | pages = 251–60 | date = Jul 2002 | pmid = 12150932 | doi = 10.1016/S0092-8674(02)00825-5 }}</ref><ref name="pmid15591021">{{cite journal | vauthors = Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V | title = The orphan receptor Rev-erbalpha gene is a target of the circadian clock pacemaker | journal = Journal of Molecular Endocrinology | volume = 33 | issue = 3 | pages = 585–608 | date = Dec 2004 | pmid = 15591021 | doi = 10.1677/jme.1.01554 | pmc = 3770723 }}</ref>


==Gene and protein structure==
==Gene and protein structure==
Rev-erbα is transcribed from the opposite strand of the [[thyroid hormone receptor alpha|thyroid receptor α]] (c-erbAα) gene on chromosome 17, with a 269-nucleotide overlap between the two transcripts.<ref name="pmid2165488"/>  The other mammalian [[protein isoform|isoform]] of the receptor, [[Rev-ErbA beta|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 [[transcription (genetics)|transcripts]]. Two promoters govern the expression of the Rev-erbα gene in human and rat, generating two [[messenger RNA|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.  
Rev-erbα is transcribed from the opposite strand of the [[thyroid hormone receptor alpha|thyroid receptor α]] (c-erbAα) gene on chromosome 17, with a 269-nucleotide overlap between the two transcripts.<ref name="pmid2165488"/>  The other mammalian [[protein isoform|isoform]] of the receptor, [[Rev-ErbA beta|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 [[transcription (genetics)|transcripts]]. Two promoters govern the expression of the Rev-erbα gene in human and rat, generating two [[messenger RNA|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 [[alpha helix|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.<ref name="pmid17870090">{{cite journal | vauthors = Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Ryu SE | title = Structural insight into the constitutive repression function of the nuclear receptor Rev-erbbeta | journal = Journal of Molecular Biology | volume = 373 | issue = 3 | pages = 735–44 | date = Oct 2007 | pmid = 17870090 | doi = 10.1016/j.jmb.2007.08.037 }}</ref>  Interestingly, all members of the Rev-erb family bind [[heme]], which may act as a ligand to regulate their transcriptional activity.<ref name="pmid18037887">{{cite journal | vauthors = Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F | title = Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 12 | pages = 1207–13 | date = Dec 2007 | pmid = 18037887 | pmc = 2743565 | doi = 10.1038/nsmb1344 }}</ref>
The Rev-erbα protein is structurally unique from other nuclear receptors, in that it lacks [[alpha helix|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.<ref name="pmid17870090">{{cite journal | vauthors = Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Ryu SE | title = Structural insight into the constitutive repression function of the nuclear receptor Rev-erbbeta | journal = Journal of Molecular Biology | volume = 373 | issue = 3 | pages = 735–44 | date = Oct 2007 | pmid = 17870090 | doi = 10.1016/j.jmb.2007.08.037 }}</ref>  All members of the Rev-erb family bind [[heme]], which may act as a ligand to regulate their transcriptional activity.<ref name="pmid18037887">{{cite journal | vauthors = Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F | title = Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 12 | pages = 1207–13 | date = Dec 2007 | pmid = 18037887 | pmc = 2743565 | doi = 10.1038/nsmb1344 }}</ref>


==Physiologic function==
==Physiologic function==

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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.[1]

Rev-erbα is a member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor.[2] 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.[3][4]

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.[2] 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.[5] All members of the Rev-erb family bind heme, which may act as a ligand to regulate their transcriptional activity.[6]

Physiologic function

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.[7] 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,[8] and inflammation.[9]

Rev-erbα mRNA is induced during adipogenesis and is highly expressed in adipose tissue.[10] 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.[11] More recently, a study showed that the deletion of Rev-erbα in mice alters glucose and lipid metabolism and leads to obesity.[12]

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

References

  1. ↑ Lazar MA, Jones KE, Chin WW (Mar 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 and Cell Biology. 9 (2): 77–83. doi:10.1089/dna.1990.9.77. PMID 1971514.
  2. ↑ 2.0 2.1 Lazar MA, Hodin RA, Cardona G, Chin WW (Aug 1990). "Gene expression from the c-erbA alpha/Rev-ErbA alpha genomic locus. Potential regulation of alternative splicing by opposite strand transcription". The Journal of Biological Chemistry. 265 (22): 12859–63. PMID 2165488.
  3. ↑ Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (Jul 2002). "The orphan nuclear receptor REV-ERBalpha 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.
  4. ↑ Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V (Dec 2004). "The orphan receptor Rev-erbalpha gene is a target of the circadian clock pacemaker". Journal of Molecular Endocrinology. 33 (3): 585–608. doi:10.1677/jme.1.01554. PMC 3770723. PMID 15591021.
  5. ↑ Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Ryu SE (Oct 2007). "Structural insight into the constitutive repression function of the nuclear receptor Rev-erbbeta". Journal of Molecular Biology. 373 (3): 735–44. doi:10.1016/j.jmb.2007.08.037. PMID 17870090.
  6. ↑ Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F (Dec 2007). "Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta". Nature Structural & Molecular Biology. 14 (12): 1207–13. doi:10.1038/nsmb1344. PMC 2743565. PMID 18037887.
  7. ↑ Wang J, Yin L, Lazar MA (Nov 2006). "The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1". The Journal of Biological Chemistry. 281 (45): 33842–8. doi:10.1074/jbc.M607873200. PMID 16968709.
  8. ↑ Delezie J, Challet E (Dec 2011). "Interactions between metabolism and circadian clocks: reciprocal disturbances". Annals of the New York Academy of Sciences. 1243: 30–46. doi:10.1111/j.1749-6632.2011.06246.x. PMID 22211891.
  9. ↑ Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM (Sep 1994). "Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors". Molecular Endocrinology. 8 (9): 1253–61. doi:10.1210/me.8.9.1253. PMID 7838158.
  10. ↑ Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, Soncin F, Mandrup S, Fruchart JC, Fruchart-Najib J, Staels B (Sep 2003). "The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation". The Journal of Biological Chemistry. 278 (39): 37672–80. doi:10.1074/jbc.M304664200. PMID 12821652.
  11. ↑ Chawla A, Lazar MA (Aug 1993). "Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation". The Journal of Biological Chemistry. 268 (22): 16265–9. PMID 8344913.
  12. ↑ Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, Teboul M, Delaunay F, Pévet P, Challet E (Aug 2012). "The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism". FASEB Journal. 26 (8): 3321–35. doi:10.1096/fj.12-208751. PMID 22562834.
  13. ↑ Yin L, Wang J, Klein PS, Lazar MA (Feb 2006). "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock". Science. 311 (5763): 1002–5. doi:10.1126/science.1121613. PMID 16484495.

Further reading

External links

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