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Protein

Cell cycle and apoptosis regulator protein 2

Gene

Ccar2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions. Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis (By similarity). As part of a histone H3-specific methyltransferase complex may mediate ligand-dependent transcriptional activation by nuclear hormone receptors (By similarity). Inhibits SUV39H1 methyltransferase activity. Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress (By similarity) Regulates the circadian expression of the core clock components NR1D1 and ARNTL/BMAL1. Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation. Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1 (PubMed:24415752). Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization (PubMed:21030595). Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2 (PubMed:25732823). Represses the ligand-dependent transcriptional activation function of ESR2. Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway. Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3. Represses the transcriptional activator activity of BRCA1. Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro (By similarity).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator, Metalloenzyme inhibitor, Repressor

Keywords - Biological processi

Apoptosis, Biological rhythms, Cell cycle, DNA damage, mRNA processing, mRNA splicing, Transcription, Transcription regulation, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiREACT_272921. Regulation of HSF1-mediated heat shock response.

Names & Taxonomyi

Protein namesi
Recommended name:
Cell cycle and apoptosis regulator protein 2
Alternative name(s):
Cell division cycle and apoptosis regulator protein 2
Gene namesi
Name:Ccar2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:2444228. Ccar2.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity

  • Note: Recruited to chromatin, post-UV irradiation. Sequestered to the cytoplasm in the presence of MCC. Translocated to the cytoplasm during UV-induced apoptosis.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice mimic a fasted state and therefore, display an increased production of glucose. Display elevated levels of PCK1 and are glucose-intolerant in both a normal and a high-fat diet (PubMed:24415752). Mice develop more tumors including lymphomas, liver tumors, lung tumors (PubMed:25732823).2 Publications

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 922922Cell cycle and apoptosis regulator protein 2PRO_0000050814Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei35 – 351PhosphothreonineBy similarity
Modified residuei112 – 1121N6-acetyllysine; by KAT8By similarity
Modified residuei124 – 1241PhosphoserineBy similarity
Modified residuei215 – 2151N6-acetyllysine; by KAT8By similarity
Modified residuei483 – 4831PhosphothreonineBy similarity
Modified residuei568 – 5681PhosphoserineBy similarity
Cross-linki590 – 590Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2 and SUMO3)By similarity
Modified residuei626 – 6261PhosphoserineBy similarity
Modified residuei674 – 6741Phosphoserine1 Publication
Modified residuei677 – 6771Phosphoserine2 Publications
Modified residuei680 – 6801Phosphoserine2 Publications
Modified residuei686 – 6861PhosphoserineBy similarity

Post-translational modificationi

Acetylation at Lys-112 and Lys-215 by KAT8 prevents inhibitory binding to SIRT1 and increases its deacetylase activity.By similarity
Genotoxic stress induces its sumoylation and sumoylation promotes the SIRT1-CCAR2 interaction which in turn inhibits SIRT1-mediated deacetylation of p53/TP53. Sumoylation leads to transcriptional activation of p53/TP53 by sequestering SIRT1 from p53/TP53. Desumoylated by SENP1.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ8VDP4.
PaxDbiQ8VDP4.
PRIDEiQ8VDP4.

PTM databases

PhosphoSiteiQ8VDP4.

Expressioni

Gene expression databases

BgeeiQ8VDP4.
CleanExiMM_2610301G19RIK.
GenevisibleiQ8VDP4. MM.

Interactioni

Subunit structurei

Component of the DBIRD complex. Interacts with ZNF326/ZIRD; the interaction is direct. Interacts (via N-terminus) with SIRT1, which inhibits the deacetylation of substrates. Interacts (via N-terminus) with SUV39H1; this interaction abolishes the interaction with SIRT1. Part of a complex composed at least of ASCL2, C11orf30/EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Interacts with NR1D1. Interacts (via N-terminus) with ESR1 and ESR2. Interacts (via N-terminus) with HDAC3 (via C-terminus). Interacts with HDAC1 and MED2F. Interacts with MCC. Interacts (via N-terminus) with NR1H2 and NR1H3 in a ligand-independent manner. Interacts with CSNK2A1. Interacts (via N-terminus) with p53/TP53. Interacts (via N-terminus) with BRCA1 (via the BRCT domains). Interacts (via N-terminus) with CHEK2 (via protein kinase domain). Interacts with PSEM3. Interacts (via N-terminus) with PSIA3 and SENP1. The sumoylated form shows a preferential interaction with SIRT1 as compared to its unmodified form (By similarity).By similarity5 Publications

Protein-protein interaction databases

BioGridi230123. 2 interactions.
IntActiQ8VDP4. 6 interactions.
MINTiMINT-4119906.
STRINGi10090.ENSMUSP00000036924.

Structurei

3D structure databases

ProteinModelPortaliQ8VDP4.
SMRiQ8VDP4. Positions 58-117.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni609 – 66961Interaction with MCCBy similarityAdd
BLAST
Regioni703 – 922220Interaction with NR1D1By similarityAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili573 – 59624Sequence AnalysisAdd
BLAST
Coiled coili828 – 89871Sequence AnalysisAdd
BLAST

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiNOG307741.
GeneTreeiENSGT00530000063672.
HOGENOMiHOG000113184.
HOVERGENiHBG081843.
InParanoidiQ8VDP4.
OMAiMSQFKRQ.
OrthoDBiEOG7CK365.
PhylomeDBiQ8VDP4.
TreeFamiTF316387.

Family and domain databases

InterProiIPR025224. CCAR1/CCAR2.
IPR028811. CCAR2.
IPR025954. DBC1/CARP1_inactive_NUDIX_dom.
IPR025223. S1-like_RNA-bd_dom.
[Graphical view]
PANTHERiPTHR14304. PTHR14304. 1 hit.
PTHR14304:SF12. PTHR14304:SF12. 1 hit.
PfamiPF14443. DBC1. 1 hit.
PF14444. S1-like. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q8VDP4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSQFKRQRIN PLPGGRNFSG AASTSLLGPP PGLLTPPVAT DLSQNARHLQ
60 70 80 90 100
SGEKQRVFTG IVTSLHDYFG VVDEEVFFQL SVVKGRLPQL GEKVLVKAAY
110 120 130 140 150
NPGQAVPWNA VKVQTLSNQP LLKSPAPPLL HVAALGQKQG ILGAQPQLIF
160 170 180 190 200
QPHRIPPLFP QKPLSLFQTS HTLHLSHLNR FPARGPHGRL DQGRSDDYDS
210 220 230 240 250
KKRKQRAGGE PWGAKKPRHD LSPYRVHLTP YTVDSPTCDF LELQRRYRSL
260 270 280 290 300
LVPSDFLSVH LSWLSAFPLG QPFSLHHPSR IQVSSEKEAA PDTGAEPSPE
310 320 330 340 350
DSDPTYSSKV LLLSSPGLEE FYRCCMLFVD DMAEPRETPE HPLKQLKFLL
360 370 380 390 400
GRKEEEAVLV GGEWSPSLDG LDPQADPQVL VRTAIRCAQA QTGIDLSTCT
410 420 430 440 450
KWWRFAEFQY LQPGPPRQLH TVVVYLPDVW TIMPTLEEWE ALCQQKATEA
460 470 480 490 500
APQPHEASGE AEATEQAPDV SEQADTSKQN TETMEATTQQ DVDTDLPEAP
510 520 530 540 550
PPPLEPAVMA RPRCVNLSLY GIVEDRRPKE RISFEVVVLA ELFVEMLQRD
560 570 580 590 600
FGYRIYKTLL SLPEKVVSPP EPEKEEAAKE DAVKEEEAVK EEAVKVSKDE
610 620 630 640 650
VQNEGTAAES DSPLKEDGLL PKRPSSGGEE EEKARGEAAE DLCEMALDPD
660 670 680 690 700
LLLLRDDGED EFAGAKLEET EVRSVASNQS EMEYSSLQDM PKELDPSTVL
710 720 730 740 750
PLDCLLAFVF FDANWCGYLH RRDLERVLLT LGIRLSAEQA KQLVSRVVAQ
760 770 780 790 800
NICQYRSLQY SRAEVLDDGL PEDVLFGNLD LLPPSGKSTK PGAAPTEHKG
810 820 830 840 850
LVPHNGSLIN VGSLLQRAEQ QDSGRLYLEN KIHTLELKLE ESHNRFSATE
860 870 880 890 900
VTNKTLAAEM QELRARLAEA EETARTAERQ KNQLQRQMQD FRRRLTPLHL
910 920
EMQRIVEKAD SWVEKEEPTP SN
Length:922
Mass (Da):103,002
Last modified:March 1, 2004 - v2
Checksum:i19F43ECEE58F461C
GO

Sequence cautioni

The sequence BAC27420.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAC34139.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti527 – 5293RPK → HAS in AAH25471 (PubMed:15489334).Curated
Sequence conflicti720 – 7201H → L in AAH38346 (PubMed:15489334).Curated
Sequence conflicti812 – 8121G → R in BAC27420 (PubMed:16141072).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK031472 mRNA. Translation: BAC27420.1. Different initiation.
AK050238 mRNA. Translation: BAC34139.2. Different initiation.
BC021475 mRNA. Translation: AAH21475.2.
BC025471 mRNA. Translation: AAH25471.1.
BC038346 mRNA. Translation: AAH38346.1.
CCDSiCCDS49534.1.
RefSeqiNP_666167.3. NM_146055.3.
XP_006518959.1. XM_006518896.2.
UniGeneiMm.218284.

Genome annotation databases

EnsembliENSMUST00000035612; ENSMUSP00000036924; ENSMUSG00000033712.
GeneIDi219158.
KEGGimmu:219158.
UCSCiuc007unf.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK031472 mRNA. Translation: BAC27420.1. Different initiation.
AK050238 mRNA. Translation: BAC34139.2. Different initiation.
BC021475 mRNA. Translation: AAH21475.2.
BC025471 mRNA. Translation: AAH25471.1.
BC038346 mRNA. Translation: AAH38346.1.
CCDSiCCDS49534.1.
RefSeqiNP_666167.3. NM_146055.3.
XP_006518959.1. XM_006518896.2.
UniGeneiMm.218284.

3D structure databases

ProteinModelPortaliQ8VDP4.
SMRiQ8VDP4. Positions 58-117.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi230123. 2 interactions.
IntActiQ8VDP4. 6 interactions.
MINTiMINT-4119906.
STRINGi10090.ENSMUSP00000036924.

PTM databases

PhosphoSiteiQ8VDP4.

Proteomic databases

MaxQBiQ8VDP4.
PaxDbiQ8VDP4.
PRIDEiQ8VDP4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000035612; ENSMUSP00000036924; ENSMUSG00000033712.
GeneIDi219158.
KEGGimmu:219158.
UCSCiuc007unf.1. mouse.

Organism-specific databases

CTDi57805.
MGIiMGI:2444228. Ccar2.

Phylogenomic databases

eggNOGiNOG307741.
GeneTreeiENSGT00530000063672.
HOGENOMiHOG000113184.
HOVERGENiHBG081843.
InParanoidiQ8VDP4.
OMAiMSQFKRQ.
OrthoDBiEOG7CK365.
PhylomeDBiQ8VDP4.
TreeFamiTF316387.

Enzyme and pathway databases

ReactomeiREACT_272921. Regulation of HSF1-mediated heat shock response.

Miscellaneous databases

NextBioi376623.
PROiQ8VDP4.
SOURCEiSearch...

Gene expression databases

BgeeiQ8VDP4.
CleanExiMM_2610301G19RIK.
GenevisibleiQ8VDP4. MM.

Family and domain databases

InterProiIPR025224. CCAR1/CCAR2.
IPR028811. CCAR2.
IPR025954. DBC1/CARP1_inactive_NUDIX_dom.
IPR025223. S1-like_RNA-bd_dom.
[Graphical view]
PANTHERiPTHR14304. PTHR14304. 1 hit.
PTHR14304:SF12. PTHR14304:SF12. 1 hit.
PfamiPF14443. DBC1. 1 hit.
PF14444. S1-like. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Liver and Testis.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Mammary tumor.
  3. Lubec G., Sunyer B., Chen W.-Q.
    Submitted (JAN-2009) to UniProtKB
    Cited for: PROTEIN SEQUENCE OF 226-248, IDENTIFICATION BY MASS SPECTROMETRY.
    Strain: OF1.
    Tissue: Hippocampus.
  4. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-677 AND SER-680, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic brain.
  5. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-674; SER-677 AND SER-680, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  6. "Inhibition of SUV39H1 methyltransferase activity by DBC1."
    Li Z., Chen L., Kabra N., Wang C., Fang J., Chen J.
    J. Biol. Chem. 284:10361-10366(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS SUV39H1 INHIBITOR, INTERACTION WITH SUV39H1.
  7. "HDAC3 is negatively regulated by the nuclear protein DBC1."
    Chini C.C., Escande C., Nin V., Chini E.N.
    J. Biol. Chem. 285:40830-40837(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbalpha."
    Chini C.C., Escande C., Nin V., Chini E.N.
    Biochem. J. 451:453-461(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH NR1D1.
  9. "Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis."
    Nin V., Chini C.C., Escande C., Capellini V., Chini E.N.
    J. Biol. Chem. 289:5518-5527(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  10. "DBC1 functions as a tumor suppressor by regulating p53 stability."
    Qin B., Minter-Dykhouse K., Yu J., Zhang J., Liu T., Zhang H., Lee S., Kim J., Wang L., Lou Z.
    Cell Rep. 10:1324-1334(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiCCAR2_MOUSE
AccessioniPrimary (citable) accession number: Q8VDP4
Secondary accession number(s): Q6PIB1
, Q8BWR5, Q8C0F0, Q8R3G6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2006
Last sequence update: March 1, 2004
Last modified: June 24, 2015
This is version 105 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.