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Showing Protein Nuclear receptor subfamily 1 group D member 1 (HMDBP12681)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 2 metabolites
Identification
HMDB Protein ID HMDBP12681
Secondary Accession Numbers None
Name Nuclear receptor subfamily 1 group D member 1
Synonyms
  1. Rev-erbA-alpha
  2. V-erbA-related protein 1
  3. EAR-1
Gene Name NR1D1
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC1 and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity).
Pathways
  • Circadian rhythm
Reactions Not Available
GO Classification
Biological Process
regulation of lipid metabolic process
circadian temperature homeostasis
negative regulation of astrocyte activation
negative regulation of microglial cell activation
negative regulation of neuroinflammatory response
negative regulation of toll-like receptor 4 signaling pathway
negative regulation of inflammatory response
positive regulation of bile acid biosynthetic process
proteasomal protein catabolic process
regulation of circadian sleep/wake cycle
regulation of insulin secretion involved in cellular response to glucose stimulus
regulation of type B pancreatic cell proliferation
response to leptin
negative regulation of I-kappaB kinase/NF-kappaB cascade
cellular response to tumor necrosis factor
hormone-mediated signaling pathway
regulation of fat cell differentiation
cellular response to lipopolysaccharide
cellular response to interleukin-1
negative regulation of transcription, DNA-dependent
positive regulation of transcription, DNA-dependent
negative regulation of transcription from RNA polymerase II promoter
positive regulation of transcription from RNA polymerase II promoter
cell differentiation
cholesterol homeostasis
cellular glucose homeostasis
regulation of circadian rhythm
circadian regulation of gene expression
glycogen biosynthetic process
circadian rhythm
transcription initiation from RNA polymerase II promoter
negative regulation of cold-induced thermogenesis
protein destabilization
Cellular Component
cytoplasm
dendrite
nucleus
nucleoplasm
dendritic spine
chromatin
nuclear body
Molecular Function
DNA-binding transcription repressor activity, RNA polymerase II-specific
RNA polymerase II transcription regulatory region sequence-specific DNA binding
transcription corepressor binding
zinc ion binding
steroid hormone receptor activity
heme binding
DNA-binding transcription factor activity, RNA polymerase II-specific
E-box binding
RNA polymerase II core promoter proximal region sequence-specific DNA binding
nuclear receptor activity
sequence-specific double-stranded DNA binding
transcription regulatory region sequence-specific DNA binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 614
Molecular Weight 66804.595
Theoretical pI 8.493
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P20393
UniProtKB/Swiss-Prot Entry Name NR1D1_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Laudet V, Begue A, Henry-Duthoit C, Joubel A, Martin P, Stehelin D, Saule S: Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene. Nucleic Acids Res. 1991 Mar 11;19(5):1105-12. [PubMed:1850510 ]
  3. Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, Yamamoto T: Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell. 1989 Apr 7;57(1):31-9. [PubMed:2539258 ]
  4. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [PubMed:24275569 ]
  5. Lazar MA, Jones KE, Chin WW: 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. 1990 Mar;9(2):77-83. doi: 10.1089/dna.1990.9.77. [PubMed:1971514 ]
  6. Coste H, Rodriguez JC: Orphan nuclear hormone receptor Rev-erbalpha regulates the human apolipoprotein CIII promoter. J Biol Chem. 2002 Jul 26;277(30):27120-9. doi: 10.1074/jbc.M203421200. Epub 2002 May 20. [PubMed:12021280 ]
  7. Yin L, Lazar MA: The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol Endocrinol. 2005 Jun;19(6):1452-9. doi: 10.1210/me.2005-0057. Epub 2005 Mar 10. [PubMed:15761026 ]
  8. Wang J, Yin L, Lazar MA: The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. J Biol Chem. 2006 Nov 10;281(45):33842-8. doi: 10.1074/jbc.M607873200. Epub 2006 Sep 11. [PubMed:16968709 ]
  9. Yin L, Wang J, Klein PS, Lazar MA: Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science. 2006 Feb 17;311(5763):1002-5. doi: 10.1126/science.1121613. [PubMed:16484495 ]
  10. Wang J, Li Y, Zhang M, Liu Z, Wu C, Yuan H, Li YY, Zhao X, Lu H: A zinc finger HIT domain-containing protein, ZNHIT-1, interacts with orphan nuclear hormone receptor Rev-erbbeta and removes Rev-erbbeta-induced inhibition of apoCIII transcription. FEBS J. 2007 Oct;274(20):5370-81. doi: 10.1111/j.1742-4658.2007.06062.x. Epub 2007 Sep 24. [PubMed:17892483 ]
  11. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA: Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science. 2007 Dec 14;318(5857):1786-9. doi: 10.1126/science.1150179. Epub 2007 Nov 15. [PubMed:18006707 ]
  12. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA: Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha. Genes Dev. 2009 Sep 15;23(18):2201-9. doi: 10.1101/gad.1825809. Epub 2009 Aug 26. [PubMed:19710360 ]
  13. Yin L, Wu N, Lazar MA: Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal. 2010 Apr 16;8:e001. doi: 10.1621/nrs.08001. [PubMed:20414452 ]
  14. Yin L, Joshi S, Wu N, Tong X, Lazar MA: E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11614-9. doi: 10.1073/pnas.1000438107. Epub 2010 Jun 7. [PubMed:20534529 ]
  15. Valnegri P, Khelfaoui M, Dorseuil O, Bassani S, Lagneaux C, Gianfelice A, Benfante R, Chelly J, Billuart P, Sala C, Passafaro M: A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbalpha. Nat Neurosci. 2011 Aug 28;14(10):1293-301. doi: 10.1038/nn.2911. [PubMed:21874017 ]
  16. Lamia KA, Papp SJ, Yu RT, Barish GD, Uhlenhaut NH, Jonker JW, Downes M, Evans RM: Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature. 2011 Dec 14;480(7378):552-6. doi: 10.1038/nature10700. [PubMed:22170608 ]
  17. Crumbley C, Burris TP: Direct regulation of CLOCK expression by REV-ERB. PLoS One. 2011 Mar 29;6(3):e17290. doi: 10.1371/journal.pone.0017290. [PubMed:21479263 ]
  18. Stratmann M, Schibler U: REV-ERBs: more than the sum of the individual parts. Cell Metab. 2012 Jun 6;15(6):791-3. doi: 10.1016/j.cmet.2012.05.006. [PubMed:22682217 ]
  19. Ripperger JA, Albrecht U: REV-ERB-erating nuclear receptor functions in circadian metabolism and physiology. Cell Res. 2012 Sep;22(9):1319-21. doi: 10.1038/cr.2012.81. Epub 2012 May 22. [PubMed:22613952 ]
  20. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, Farrow SN, Else KJ, Singh D, Ray DW, Loudon AS: The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):582-7. doi: 10.1073/pnas.1106750109. Epub 2011 Dec 19. [PubMed:22184247 ]
  21. Chini CC, Escande C, Nin V, Chini EN: DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbalpha. Biochem J. 2013 May 1;451(3):453-61. doi: 10.1042/BJ20121085. [PubMed:23398316 ]
  22. Nin V, Chini CC, Escande C, Capellini V, Chini EN: Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis. J Biol Chem. 2014 Feb 28;289(9):5518-27. doi: 10.1074/jbc.M113.512913. Epub 2014 Jan 10. [PubMed:24415752 ]
  23. DeBruyne JP, Baggs JE, Sato TK, Hogenesch JB: Ubiquitin ligase Siah2 regulates RevErbalpha degradation and the mammalian circadian clock. Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12420-5. doi: 10.1073/pnas.1501204112. Epub 2015 Sep 21. [PubMed:26392558 ]
  24. Zhao X, Hirota T, Han X, Cho H, Chong LW, Lamia K, Liu S, Atkins AR, Banayo E, Liddle C, Yu RT, Yates JR 3rd, Kay SA, Downes M, Evans RM: Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalpha Degradation. Cell. 2016 Jun 16;165(7):1644-1657. doi: 10.1016/j.cell.2016.05.012. Epub 2016 May 26. [PubMed:27238018 ]