“Rev-ErbA alpha”的意思、由来-开放百科全书

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. ^{{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 }}
2. ^¹{{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 }}
3. ^{{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 }}
4. ^{{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 }}
5. ^{{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 }}
6. ^{{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 }}
7. ^{{cite journal | vauthors = Wang J, Yin L, Lazar MA | title = The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1 | journal = The Journal of Biological Chemistry | volume = 281 | issue = 45 | pages = 33842–8 | date = Nov 2006 | pmid = 16968709 | doi = 10.1074/jbc.M607873200 }}
8. ^{{cite journal | vauthors = Delezie J, Challet E | title = Interactions between metabolism and circadian clocks: reciprocal disturbances | journal = Annals of the New York Academy of Sciences | volume = 1243 | issue = | pages = 30–46 | date = Dec 2011 | pmid = 22211891 | pmc = | doi = 10.1111/j.1749-6632.2011.06246.x }}
9. ^{{cite journal | vauthors = Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM | title = Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors | journal = Molecular Endocrinology | volume = 8 | issue = 9 | pages = 1253–61 | date = Sep 1994 | pmid = 7838158 | doi = 10.1210/me.8.9.1253 }}
10. ^{{cite journal | vauthors = Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, Soncin F, Mandrup S, Fruchart JC, Fruchart-Najib J, Staels B | title = The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 39 | pages = 37672–80 | date = Sep 2003 | pmid = 12821652 | doi = 10.1074/jbc.M304664200 }}
11. ^{{cite journal | vauthors = Chawla A, Lazar MA | title = Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation | journal = The Journal of Biological Chemistry | volume = 268 | issue = 22 | pages = 16265–9 | date = Aug 1993 | pmid = 8344913 | doi = | url = http://www.jbc.org/cgi/content/abstract/268/22/16265 }}
12. ^{{cite journal | vauthors = Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, Teboul M, Delaunay F, Pévet P, Challet E | title = The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism | journal = FASEB Journal | volume = 26 | issue = 8 | pages = 3321–35 | date = Aug 2012 | pmid = 22562834 | pmc = | doi = 10.1096/fj.12-208751 }}
13. ^{{cite journal | vauthors = Yin L, Wang J, Klein PS, Lazar MA | title = Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock | journal = Science | volume = 311 | issue = 5763 | pages = 1002–5 | date = Feb 2006 | pmid = 16484495 | doi = 10.1126/science.1121613 }}

Gene and protein structure

Physiologic function

References

Further reading

External links