Circadian Clock (Homo sapiens)

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16, 28, 30, 43675, 18, 42, 5022, 7036, 6110, 11, 17272113, 34157125, 39, 54, 60247, 19, 21, 26, 41...29, 557, 583153, 56473, 6, 14, 204437, 51, 56636933, 64, 66, 7212, 594, 22, 26, 461, 29p-CRY1/2[nucleoplasm]PPARA:RXRACoactivator Complex[nucleoplasm]mitochondrial outer membranep-CLOCK/p-NPAS2[nucleoplasm]MEF2C/D:PPARGC1A[nucleoplasm]p-CRY:p-PER:Kinase[nucleoplasm]BMAL2:CLOCK[nucleoplasm]Coactivators ofPPARalpha[nucleoplasm]p-CLOCK/p-NPAS2[nucleoplasm]BMAL1:CLOCK/NPAS2:CRY:PER[nucleoplasm]p-BMAL1:p-CLOCK/NPAS2:DNA[nucleoplasm]p-CRY:p-PER:Kinase[cytosol]Glucocorticoidreceptor:DexamethasoneComplex[nucleoplasm]SCF-beta-TrCP1complex [cytosol]PER1/2 [cytosol]CRY1/2 [cytosol]p-CRY1/2[nucleoplasm]p-BMAL1:p-CLOCK/NPAS2:DNA[nucleoplasm]p-S-PER1,2[nucleoplasm]PPARA: Fatty AcidComplex (ActivatedPPARA) [nucleoplasm]cytosolCLOCK/NPAS2[cytosol]p-CRY1/2 [cytosol]BMAL1:CLOCK/NPAS2[cytosol]NR1D1(REV-ERBA):heme[nucleoplasm]ROR-alpha:Coactivator[nucleoplasm]NR1D1(REV-ERBA):heme:Corepressor[nucleoplasm]FBXL3:CRY[nucleoplasm]CRY:PER:Kinase[cytosol]MEF2C/D[nucleoplasm]Ligands of PPARA[nucleoplasm]p-PER1/2 [cytosol]nucleoplasmPER1/2 [cytosol]p-CRY:p-PER:Kinase[nucleoplasm]p-CRY1/2[nucleoplasm]endoplasmic reticulum lumenActivated PPARA:RXRAHeterodimer[nucleoplasm]p-S-PER1,2[nucleoplasm]BMAL1:CLOCK/NPAS2:CRY[cytosol]CLOCK/NPAS2[cytosol]CRY1/2 [cytosol]Beta-TrCP1:PER[cytosol]BMAL1:CLOCK/NPAS2[cytosol]CRY:PER:Kinasep-S133-CREB1NCOA2 [nucleoplasm]NPAS2 [cytosol]ferriheme bCREBBP(2-2442)[nucleoplasm]p-S-CLOCK[nucleoplasm]PPARA [nucleoplasm]LINA [nucleoplasm]p-S-NPAS2[nucleoplasm]NR1D1(REV-ERBA):heme:CorepressorBMAL2:CLOCKp-S-ARNTL[nucleoplasm]ubiquitinCRY2 [cytosol]TBL1X [nucleoplasm]CLOCKSREBF1(1-1147)CRY1 [cytosol]SKP1 [cytosol]p-S-CRY2[nucleoplasm]MEF2D [nucleoplasm]CLOCK [cytosol]ELOVL3RORANR1D1 [nucleoplasm]HDAC3 [nucleoplasm]CLOCK [cytosol]p-S-PER2[nucleoplasm]CSNK1E/CSNK1DBMAL1:CLOCK/NPAS2CARM1(2-608)[nucleoplasm]p-S-CRY1[nucleoplasm]TGS1 [nucleoplasm]RXRA [nucleoplasm]PER1 [cytosol]p-S-PER1[nucleoplasm]HIF1ABHLHE41CUL1 [cytosol]p-S-PER2[nucleoplasm]p-PER1/2CLOCK [nucleoplasm]HDAC3BMAL1:CLOCK/NPAS2:CRY:PERp-S-CRY2 [cytosol]ARNTL2 [nucleoplasm]BTRCp-BMAL1:p-CLOCK/NPAS2:DNAMEF2C [nucleoplasm]SERPINE1NR3C1 [nucleoplasm]SMARCD3[nucleoplasm]EPA [nucleoplasm]p-CRY1/2NCOR1NPAS2 [cytosol]ferriheme b[nucleoplasm]ub-p-CRY1/2p-CRY:p-PER:KinaseBeta-TrCP1:PERp-S-CRY1[nucleoplasm]UbPER1 [cytosol]p-PPARGC1AGlucocorticoidreceptor:DexamethasoneComplexp-S-PER1 [cytosol]MED1 [nucleoplasm]RORA [nucleoplasm]PPARGC1A[nucleoplasm]FBXL3 [nucleoplasm]p-S-CLOCK[nucleoplasm]Palm [nucleoplasm]FBXL3:CRYCRY1PER1PPARAp-S-CRY2[nucleoplasm]DBPPPARA:RXRACoactivator ComplexFBXL3PER2 [cytosol]pro-factor VIIARNTL [cytosol]NPAS2RORE (DNA)CRY1 [cytosol]AA [nucleoplasm]BTRC [cytosol]CHD9 [nucleoplasm]NAMPTAVP(20-28)PPARGC1A[nucleoplasm]PER2 [cytosol]CLOCK/NPAS2NCOA6 [nucleoplasm]p-S-PER1[nucleoplasm]p-CRY:p-PER:Kinasep-S-CRY1 [cytosol]ROR-alpha:CoactivatorCRY2NR1D1ALA [nucleoplasm]ARNTL [cytosol]DEXA [nucleoplasm]PER2CRY2 [cytosol]TBL1XR1[nucleoplasm]BMAL1:CLOCK/NPAS2:CRYSCF-beta-TrCP1complexBTRC [cytosol]MEF2C/D:PPARGC1APPARGC1APER1/2CCRN4LEP300(1-2414)[nucleoplasm]p-T69,T71-ATF2NCOA1 [nucleoplasm]p-S-ARNTL[nucleoplasm]EP300(1-2414)p-S-NPAS2[nucleoplasm]ARNTLp-S-CRY2[nucleoplasm]NCOR1 [nucleoplasm]E-box (DNA)BHLHE40HELZ2 [nucleoplasm]CPT1ACRY1/2p-S-CRY1[nucleoplasm]p-S-PER2 [cytosol]ub-p-PER1/245, 65, 68217, 2340, 4918, 42, 509321417, 238, 382117, 2335, 52, 57


At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning.
Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA, both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1.
BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening.
PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.
The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients.Original Pathway at Reactome:

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101648view11:51, 1 November 2018ReactomeTeamreactome version 66
101184view21:39, 31 October 2018ReactomeTeamreactome version 65
100710view20:11, 31 October 2018ReactomeTeamreactome version 64
100260view16:56, 31 October 2018ReactomeTeamreactome version 63
99813view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93971view13:48, 16 August 2017ReactomeTeamreactome version 61
93571view11:27, 9 August 2017ReactomeTeamreactome version 61
87160view19:15, 18 July 2016MkutmonOntology Term : 'regulatory pathway' added !
86673view09:23, 11 July 2016ReactomeTeamreactome version 56
83282view10:37, 18 November 2015ReactomeTeamVersion54
81401view12:55, 21 August 2015ReactomeTeamVersion53
76871view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76576view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75909view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75609view10:46, 10 June 2014ReactomeTeamReactome 48 Update
74964view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74608view08:39, 30 April 2014ReactomeTeamReactome46
42020view21:50, 4 March 2011MaintBotAutomatic update
39823view05:51, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
AA [nucleoplasm]MetaboliteCHEBI:15843 (ChEBI)
ALA [nucleoplasm]MetaboliteCHEBI:27432 (ChEBI)
ARNTL [cytosol]ProteinO00327 (Uniprot-TrEMBL)
ARNTL2 [nucleoplasm]ProteinQ8WYA1 (Uniprot-TrEMBL)
ARNTLProteinO00327 (Uniprot-TrEMBL)
AVP(20-28)ProteinP01185 (Uniprot-TrEMBL)
BHLHE40ProteinO14503 (Uniprot-TrEMBL)
BHLHE41ProteinQ9C0J9 (Uniprot-TrEMBL)
BMAL1:CLOCK/NPAS2:CRY:PERComplexREACT_26318 (Reactome)
BMAL1:CLOCK/NPAS2:CRYComplexREACT_25684 (Reactome)
BMAL1:CLOCK/NPAS2ComplexREACT_26547 (Reactome) BMAL1 (ARNTL) contains both a nuclear localization signal and a nuclear export signal. The shuttling of BMAL1 between the nucleus and cytoplasm is important for transactivation by BMAL1:CLOCK/NPAS2 and degradation of BMAL1:CLOCK/NPAS2. BMAL1 initially forms a heterodimer with CLOCK or NPAS2 in the cytosol. The heterodimer is then phosphorylated and translocated into the nucleus.
BMAL2:CLOCKComplexREACT_26482 (Reactome)
BTRC [cytosol]ProteinQ9Y297 (Uniprot-TrEMBL)
BTRCProteinQ9Y297 (Uniprot-TrEMBL)
Beta-TrCP1:PERComplexREACT_27062 (Reactome)
CARM1(2-608) [nucleoplasm]ProteinQ86X55 (Uniprot-TrEMBL)
CCRN4LProteinQ9UK39 (Uniprot-TrEMBL)
CHD9 [nucleoplasm]ProteinQ3L8U1 (Uniprot-TrEMBL)
CLOCK [cytosol]ProteinO15516 (Uniprot-TrEMBL)
CLOCK [nucleoplasm]ProteinO15516 (Uniprot-TrEMBL)
CLOCK/NPAS2ProteinREACT_26942 (Reactome)
CLOCKProteinO15516 (Uniprot-TrEMBL)
CPT1AProteinP50416 (Uniprot-TrEMBL)
CREBBP(2-2442) [nucleoplasm]ProteinQ92793 (Uniprot-TrEMBL)
CRY1 [cytosol]ProteinQ16526 (Uniprot-TrEMBL)
CRY1/2ProteinREACT_26101 (Reactome)
CRY1ProteinQ16526 (Uniprot-TrEMBL)
CRY2 [cytosol]ProteinQ49AN0 (Uniprot-TrEMBL)
CRY2ProteinQ49AN0 (Uniprot-TrEMBL)
CRY:PER:KinaseComplexREACT_26725 (Reactome) As inferred from mouse, PER proteins can form homodimers and CRY proteins can form heterodimers with PER proteins. CRY and PER proteins may therefore form trimers (PER:PER:CRY).
CSNK1E/CSNK1DREACT_26408 (Reactome)
CUL1 [cytosol]ProteinQ13616 (Uniprot-TrEMBL)
DBPProteinQ10586 (Uniprot-TrEMBL)
DEXA [nucleoplasm]MetaboliteCHEBI:41879 (ChEBI)
E-box (DNA)REACT_25457 (Reactome) The consensus sequence of the E-box is CACGTG.
ELOVL3ProteinQ9HB03 (Uniprot-TrEMBL)
EP300(1-2414) [nucleoplasm]ProteinQ09472 (Uniprot-TrEMBL)
EP300(1-2414)ProteinQ09472 (Uniprot-TrEMBL)
EPA [nucleoplasm]MetaboliteCHEBI:28364 (ChEBI)
FBXL3 [nucleoplasm]ProteinQ9UKT7 (Uniprot-TrEMBL)
FBXL3:CRYComplexREACT_25657 (Reactome)
FBXL3ProteinQ9UKT7 (Uniprot-TrEMBL)


ComplexREACT_26089 (Reactome)
HDAC3 [nucleoplasm]ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HELZ2 [nucleoplasm]ProteinQ9BYK8 (Uniprot-TrEMBL)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
LINA [nucleoplasm]MetaboliteCHEBI:17351 (ChEBI)
MED1 [nucleoplasm]ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MEF2C [nucleoplasm]ProteinQ06413 (Uniprot-TrEMBL)
MEF2C/D:PPARGC1AComplexREACT_120029 (Reactome)
MEF2D [nucleoplasm]ProteinQ14814 (Uniprot-TrEMBL)
NAMPTProteinP43490 (Uniprot-TrEMBL)
NCOA1 [nucleoplasm]ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 [nucleoplasm]ProteinQ15596 (Uniprot-TrEMBL)
NCOA6 [nucleoplasm]ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 [nucleoplasm]ProteinO75376 (Uniprot-TrEMBL)
NCOR1ProteinO75376 (Uniprot-TrEMBL)
NPAS2 [cytosol]ProteinQ99743 (Uniprot-TrEMBL)
NPAS2ProteinQ99743 (Uniprot-TrEMBL)
NR1D1 (REV-ERBA):heme:CorepressorComplexREACT_111441 (Reactome)
NR1D1 [nucleoplasm]ProteinP20393 (Uniprot-TrEMBL)
NR1D1ProteinP20393 (Uniprot-TrEMBL)
NR3C1 [nucleoplasm]ProteinP04150 (Uniprot-TrEMBL)
PER1 [cytosol]ProteinO15534 (Uniprot-TrEMBL)
PER1/2ProteinREACT_25978 (Reactome)
PER1ProteinO15534 (Uniprot-TrEMBL)
PER2 [cytosol]ProteinO15055 (Uniprot-TrEMBL)
PER2ProteinO15055 (Uniprot-TrEMBL)
PPARA [nucleoplasm]ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator ComplexComplexREACT_20439 (Reactome)
PPARAProteinQ07869 (Uniprot-TrEMBL)
PPARGC1A [nucleoplasm]ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
Palm [nucleoplasm]MetaboliteCHEBI:15756 (ChEBI)
ROR-alpha:CoactivatorComplexREACT_111748 (Reactome)
RORA [nucleoplasm]ProteinP35398 (Uniprot-TrEMBL)
RORAProteinP35398 (Uniprot-TrEMBL)
RORE (DNA)REACT_111419 (Reactome)
RXRA [nucleoplasm]ProteinP19793 (Uniprot-TrEMBL)
SCF-beta-TrCP1 complexComplexREACT_6992 (Reactome)
SERPINE1ProteinP05121 (Uniprot-TrEMBL)
SKP1 [cytosol]ProteinP63208 (Uniprot-TrEMBL)
SMARCD3 [nucleoplasm]ProteinQ6STE5 (Uniprot-TrEMBL)
SREBF1(1-1147)ProteinP36956 (Uniprot-TrEMBL)
TBL1X [nucleoplasm]ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 [nucleoplasm]ProteinQ9BZK7 (Uniprot-TrEMBL)
TGS1 [nucleoplasm]ProteinQ96RS0 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
ferriheme b [nucleoplasm]MetaboliteCHEBI:36144 (ChEBI)
ferriheme bMetaboliteCHEBI:36144 (ChEBI)
p-BMAL1:p-CLOCK/NPAS2:DNAComplexREACT_25790 (Reactome)
p-CRY1/2ProteinREACT_26910 (Reactome)
p-CRY:p-PER:KinaseComplexREACT_25528 (Reactome)
p-CRY:p-PER:KinaseComplexREACT_26285 (Reactome)
p-PER1/2ProteinREACT_25419 (Reactome)
p-PPARGC1AREACT_119064 (Reactome)
p-S-ARNTL [nucleoplasm]ProteinO00327 (Uniprot-TrEMBL)
p-S-CLOCK [nucleoplasm]ProteinO15516 (Uniprot-TrEMBL)
p-S-CRY1 [nucleoplasm]ProteinQ16526 (Uniprot-TrEMBL)
p-S-CRY1 [cytosol]ProteinQ16526 (Uniprot-TrEMBL)
p-S-CRY2 [nucleoplasm]ProteinQ49AN0 (Uniprot-TrEMBL)
p-S-CRY2 [cytosol]ProteinQ49AN0 (Uniprot-TrEMBL)
p-S-NPAS2 [nucleoplasm]ProteinQ99743 (Uniprot-TrEMBL)
p-S-PER1 [nucleoplasm]ProteinO15534 (Uniprot-TrEMBL)
p-S-PER1 [cytosol]ProteinO15534 (Uniprot-TrEMBL)
p-S-PER2 [nucleoplasm]ProteinO15055 (Uniprot-TrEMBL)
p-S-PER2 [cytosol]ProteinO15055 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
pro-factor VIIProteinP08709 (Uniprot-TrEMBL)
ub-p-CRY1/2ProteinREACT_26499 (Reactome)
ub-p-PER1/2ProteinREACT_25524 (Reactome)
ubiquitinProteinREACT_3995 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ARNTLArrowREACT_25233 (Reactome)
ARNTLREACT_25402 (Reactome)
AVP(20-28)ArrowREACT_24929 (Reactome)
ArrowREACT_115644 (Reactome)
ArrowREACT_116112 (Reactome)
ArrowREACT_25084 (Reactome)
ArrowREACT_25123 (Reactome)
ArrowREACT_25225 (Reactome)
BHLHE40ArrowREACT_25132 (Reactome)
BHLHE41ArrowREACT_25212 (Reactome)
BMAL1:CLOCK/NPAS2:CRY:PERArrowREACT_25061 (Reactome)
BMAL1:CLOCK/NPAS2:CRYArrowREACT_25234 (Reactome)
BMAL1:CLOCK/NPAS2ArrowREACT_25402 (Reactome)
BMAL1:CLOCK/NPAS2REACT_25029 (Reactome)
BMAL1:CLOCK/NPAS2REACT_25234 (Reactome)
BMAL2:CLOCKArrowREACT_25123 (Reactome)
BTRCArrowREACT_25143 (Reactome)
BTRCREACT_25088 (Reactome)
Beta-TrCP1:PERArrowREACT_25088 (Reactome)
Beta-TrCP1:PERREACT_25143 (Reactome)
CCRN4LArrowREACT_25395 (Reactome)
CLOCK/NPAS2REACT_25402 (Reactome)
CLOCKArrowREACT_118740 (Reactome)
CPT1AArrowREACT_115644 (Reactome)
CRY1/2REACT_115943 (Reactome)
CRY1/2REACT_25234 (Reactome)
CRY1ArrowREACT_25365 (Reactome)
CRY2ArrowREACT_24956 (Reactome)
CRY:PER:KinaseArrowREACT_115943 (Reactome)
CRY:PER:KinaseREACT_25125 (Reactome)
CSNK1E/CSNK1DREACT_115943 (Reactome)
CSNK1E/CSNK1Dmim-catalysisREACT_25125 (Reactome)
DBPArrowREACT_25278 (Reactome)
E-box (DNA)REACT_25029 (Reactome)
ELOVL3ArrowREACT_118691 (Reactome)
EP300(1-2414)REACT_118616 (Reactome)
FBXL3:CRYArrowREACT_25106 (Reactome)
FBXL3:CRYREACT_25378 (Reactome)
FBXL3ArrowREACT_25378 (Reactome)
FBXL3REACT_25106 (Reactome)


ArrowREACT_25321 (Reactome)
HDAC3REACT_118766 (Reactome)
HIF1AArrowREACT_118635 (Reactome)
MEF2C/D:PPARGC1AArrowREACT_118642 (Reactome)
NAMPTArrowREACT_115946 (Reactome)
NCOR1REACT_118766 (Reactome)
NPAS2ArrowREACT_116112 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorArrowREACT_118766 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_116112 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_118642 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_118691 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_118740 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_25225 (Reactome)
NR1D1 (REV-ERBA):heme:CorepressorTBarREACT_25233 (Reactome)
NR1D1ArrowREACT_25225 (Reactome)
NR1D1REACT_118766 (Reactome)
PER1/2REACT_115943 (Reactome)
PER1ArrowREACT_25237 (Reactome)
PER2ArrowREACT_25321 (Reactome)
PPARA:RXRA Coactivator ComplexArrowREACT_116112 (Reactome)
PPARAArrowREACT_25084 (Reactome)
PPARGC1AArrowREACT_118642 (Reactome)
PPARGC1AREACT_118616 (Reactome)
REACT_115644 (Reactome) The CPT1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_115943 (Reactome) CRYPTOCHROME, PERIOD, and a kinase (CKIepsilon or CKIdelta) form a ternary complex in the cytosol.
REACT_115946 (Reactome) The NAMPT (NamPRT) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer enhances transcription of NAMPT.
REACT_116112 (Reactome) The NPAS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of NPAS2 is enhanced by the RORA:Coactivator complex and repressed by the REV-ERBA:Corepressor complex.
REACT_118616 (Reactome) As inferred from mouse, RORA binds DNA and recruits the coactivators PGC-1alpha (PPARGC1A) and p300 (EP300, a histone acetylase).
REACT_118635 (Reactome) The RORA gene is transcribed to yield mRNA and the mRNA is transcribed to yield protein.
REACT_118642 (Reactome) The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPARGC1A protein is located in the nucleus where it coactivates transcription.
REACT_118691 (Reactome) The ELOVL3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_118734 (Reactome) The SREBF1 (SREBP1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_118740 (Reactome) The CLOCK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of CLOCK is repressed by REV-ERBA.
REACT_118766 (Reactome) NR1D1 (REV-ERBA) binds heme. The REV-ERBA:heme complex is then able to recruit the corepressors NCoR and HDAC3. Corepressors do not bind REV-ERBA in the absence of heme.
REACT_24929 (Reactome) The AVP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind an E-box enhancer in the promoter of the AVP gene and activate transcription of AVP.
REACT_24956 (Reactome) The CRYPTOCHROME-2 (CRY2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the CRY2 protein shows circadian rhythm in the suprachiasmatic nucleus (SCN) and in peripheral tissues. The mRNA shows circadian rhythm in muscle but not in the SCN. Expression is dependent on CLOCK.
REACT_25029 (Reactome) In mouse, BMAL1, CLOCK, and NPAS2 are phosphorylated by unknown kinases. The phosphorylation is dependent on the heterodimerization of BMAL1 with CLOCK or NPAS2. Phosphorylated BMAL1:CLOCK/NPAS2 is a much stronger transactivator of gene expression than is unphosphorylated BMAL1:CLOCK/NPAS2.
REACT_25049 (Reactome) The ternary complex containing phosphorylated CRY and PER proteins with a kinase (CSNK1D or CSNK1E) is translocated to the nucleus. Phosphorylation controls transfer to the nucleus and retention in the nucleus.
REACT_25061 (Reactome) CRY (CRY1 and CRY2) and PER (PER1, PER2, PER3) proteins form complex in the cytoplasm where they are phosphorylated by CSNK1D and CSNK1E kinases. CRY:PER complexes appear to form stable complexes with a kinase. Because of the nuclear localization signals of PER and CRY, the complexes are translocated to the nucleus where they bind BMAL1:CLOCK/NPAS2 heterodimers and inhibit the transactivation activity of BMAL1:CLOCK/NPAS2.
CRY and PER proteins are themselves transcriptionally activated by BMAL1:CLOCK/NPAS2 thus they participate in a negative loop inhibiting their own synthesis and the synthesis of other targets of BMAL1:CLOCK/NPAS2.
Experiments with two-hybrid interactions and in vitro associations show that CRY1, CRY2, and PER2 bind BMAL1 at two different sites on BMAL1. PER2 but not CRY1 or CRY2 binds CLOCK. Different combinations of PER and CRY proteins in PER:CRY complexes have different inhibitory activities.
REACT_25084 (Reactome) The PPARA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind the scond intron of the PPARA gene and activate transcription of PPARA.
REACT_25088 (Reactome) Beta-TrCP1 is an F-box type component of a particular SKP/CUL/F-Box (SCF) E3 ubiquitin ligase. Beta-TrCP1 interacts specifically with phosphorylated PER proteins and directs their polyubiquitination.
REACT_25092 (Reactome) The FACTOR VII (F7) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the F7 gene shows circadian expression due to activation by the Bmal1:Clock heterodimer.
REACT_25106 (Reactome) FBXL3 is an F-box type component of a particular SKP/CUL/F-Box E3 ubiquitin ligase. FBXL3 interacts specifically with CRY1 and CRY2 in the cytosol to direct the polyubiquitination of CRY1 and CRY2. It is unknown if FBXL3 requires phosphorylation or other modification of CRY proteins in order to bind and ubiquitinate them. Phosphorylation of CRY by Adenosine monophosphate-dependent kinase increases degradation of CRY, apparently by increasing association of CRY with FBXL3 Polyubiquitination of CRY proteins directs them to the 26S proteasome for degradation.
REACT_25123 (Reactome) The PAI-1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The PAI-1 gene shows circadian expression due to direct transcriptional activation by the BMAL1:CLOCK heterodimer and the BMAL2(CLIF, ARNTL2):CLOCK heterodimer.
REACT_25125 (Reactome) In the cytosol the kinases CSNK1D (casein kinase I delta) and CSNK1E (casein kinase I epsilon) phosphorylate PER1, PER2, CRY1, and CRY2 at multiple sites. Evidence indicates that PER:CRY complexes form a stable ternary complex with either CSNK1E or CSNK1D. Both kinases are able to bind and phosphorylate PER proteins. CSNK1E has been shown to phosphorylate CRY proteins only when they are complexed with PER proteins.
PER proteins contain a nuclear localization sequence and a nuclear export sequence allowing their movement into and out of the nucleus. Phosphorylation is required for transit of PER:CRY:kinase complexes into the nucleus and for interaction of PER proteins with the ubiquitin-mediated degradation process in the cytoplasm.
A mutation at Serine662 of PER2 is responsible for familial advanced phase sleep syndrome, however the particular kinase responsible for phosphorylating Serine662 is unknown.
REACT_25132 (Reactome) The DEC1 (BHLHE40, BHLHB2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The DEC1 gene contains E-box elements in its promoter which bind the BMAL:CLOCK heterodimer and confer circadian rhythm on its expression.
REACT_25143 (Reactome) Polyubiquitination of PER proteins is directed by the Beta-TrCP1 component of SCF E3 ubiquitin ligase. The polyubiquitinated PER proteins are recognized and degraded by the 26S proteasome. Degradation of PER proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 targets in the morning during the circadian cycle.
REACT_25212 (Reactome) The DEC2 (BHLHE41, BHLHB3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer binds E-box elements in the DEC2 promoter and activates transcription of DEC2.
REACT_25225 (Reactome) The NR1D1 (REV-ERBA) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the Rev-erba gene shows circadian expression due to transactivation by the BMAL1:CLOCK heterodimer. REV-ERBA binds the promoter of its own gene and represses its own expression (Adelmont et al. 1996).
REACT_25233 (Reactome) The BMAL1 (ARNTL) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The ROR-alpha transcription factor binds the RORE element of the BMAL1 (ARNTL) promoter and activates transcription of the BMAL1 gene. The REV-ERBA transcription factor binds the same RORE element and represses transcription of the BMAL1 gene.
REACT_25234 (Reactome) CRY1 and CRY2 bind the unphosphorylated BMAL1:CLOCK heterodimer (and by homology the BMAL1:NPAS2 heterodimer) and prolong its half-life. The unphosphorylated BMAL1:CLOCK heterodimer only weakly activates transcription and is therefore believed to competitively reduce transcription by phosphorylated BMAL1:CLOCK heterodimer. The complex of unphosphorylated BMAL1:CLOCK with CRY may contain additional components and may traffic into the nucleus.
REACT_25237 (Reactome) The PERIOD-1 (PER1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER1 gene contains E-boxes which are bound by the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER1.
REACT_25278 (Reactome) The DBP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind E-boxes in the DBP promoter and activate transcription of DBP.
REACT_25321 (Reactome) The PERIOD-2 (PER2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER2 gene contains an E-box which binds the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER2.
REACT_25365 (Reactome) The CRYPTOCHROME-1 (CRY1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CRY1 mRNA and protein show circadian expression. The promoter of the CRY1 gene contains an E-box which is bound by the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer), which activates transcription of CRY1.
REACT_25378 (Reactome) Polyubiquitination of CRY proteins is directed by the FBXL3 component of SCF E3 ubiquitin ligase. The polyubiquitinated CRY proteins are recognized and degraded by the 26S proteasome. Degradation of CRY proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 targets in the morning during the circadian cycle.
REACT_25395 (Reactome) The NOCTURNIN gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The NOCTURNIN gene shows circadian expression because the BMAL1:CLOCK heterodimer binds an E-box element in the NOCTURNIN promoter and activates transcription.
REACT_25402 (Reactome) BMAL1 (ARNTL), CLOCK, and NPAS2 are basic helix-loop-helix transcription factors. In humans BMAL1 has been demonstrated to form a heterodimer with CLOCK. In mouse, BMAL1 can form a heterodimer with either CLOCK or NPAS2. By analogy with other basic helix-loop-helix proteins the basic domain binds DNA, in this case the E-box motif, and the helix-loop-helix domains interact to form the heterodimer. BMAL1 and CLOCK/NPAS2 are codependently phosphorylated by unknown kinases after dimerization. The phosphorylation enhances transactivation activity and is inhibited by PER:CRY complexes. Both CLOCK and NPAS2 are expressed in the suprachiasmatic nucleus of the hypothalamus and act redundantly there. The tissue distributions of CLOCK and NPAS2 do not entirely overlap, however. For example, NPAS2 but not CLOCK is found in forebrain.
ROR-alpha:CoactivatorArrowREACT_115644 (Reactome)
ROR-alpha:CoactivatorArrowREACT_118616 (Reactome)
ROR-alpha:CoactivatorArrowREACT_118734 (Reactome)
ROR-alpha:CoactivatorArrowREACT_25233 (Reactome)
RORAArrowREACT_118635 (Reactome)
RORAREACT_118616 (Reactome)
RORE (DNA)REACT_118616 (Reactome)
RORE (DNA)REACT_118766 (Reactome)
SCF-beta-TrCP1 complexmim-catalysisREACT_25143 (Reactome)
SERPINE1ArrowREACT_25123 (Reactome)
SREBF1(1-1147)ArrowREACT_118734 (Reactome)
UbREACT_25143 (Reactome)
ferriheme bREACT_118766 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_115946 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_24929 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25029 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25084 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25092 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25132 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25212 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25225 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25237 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25278 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25321 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25365 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAArrowREACT_25395 (Reactome)
p-BMAL1:p-CLOCK/NPAS2:DNAREACT_25061 (Reactome)
p-CRY1/2REACT_25106 (Reactome)
p-CRY:p-PER:KinaseArrowREACT_25049 (Reactome)
p-CRY:p-PER:KinaseArrowREACT_25125 (Reactome)
p-CRY:p-PER:KinaseREACT_25049 (Reactome)
p-CRY:p-PER:KinaseREACT_25061 (Reactome)
p-PER1/2REACT_25088 (Reactome)
p-PPARGC1AArrowREACT_118642 (Reactome)
p-S133-CREB1ArrowREACT_118642 (Reactome)
p-T69,T71-ATF2ArrowREACT_118642 (Reactome)
pro-factor VIIArrowREACT_25092 (Reactome)
ub-p-CRY1/2ArrowREACT_25378 (Reactome)
ub-p-PER1/2ArrowREACT_25143 (Reactome)
ubiquitinREACT_25378 (Reactome)
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