Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

CCAR2 cell cycle and apoptosis regulator 2

Written2011-07Jian Yuan, Zhenkun Lou
Division of Oncology Research, Mayo Clinic, Rochester, MN 55902, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesKIAA1967
KIAA1967
Alias_symbol (synonym)DBC-1
DBC1
NET35
Other aliasp30DBC
HGNC (Hugo) CCAR2
LocusID (NCBI) 57805
Atlas_Id 46056
Location 8p21.3  [Link to chromosome band 8p21]
Location_base_pair Starts at 22605026 and ends at 22620470 bp from pter ( according to hg19-Feb_2009)  [Mapping CCAR2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
C5 (9q33.2) / CCAR2 (8p21.3)CCAR2 (8p21.3) / CCAR2 (8p21.3)CCAR2 (8p21.3) / FGFR2 (10q26.13)
CCAR2 (8p21.3) / PKD1P2 (6p13.11)CCAR2 (8p21.3) / SORBS3 (8p21.3)FGFR2 (10q26.13) / CCAR2 (8p21.3)
FGFR3 (4p16.3) / CCAR2 (8p21.3)XRRA1 (11q13.4) / CCAR2 (8p21.3)

DNA/RNA

 
  Adapted from http://genome.ucsc.edu.
Description This gene can be found on chromosome 8 at location 22462539-22477984.
Transcription The DNA sequence contains 21 exons and the transcript length is 4012 bps translated to a 923 residues protein.

Protein

 
Description Human KIAA1967/p30 DBC encodes a 923 amino acids protein with a leucine zipper motif, a Nudix domain, an EF hand motif and a coiled coil domain.
Expression KIAA1967/p30 DBC is widely expressed in multiple tissues.
Localisation p30 DBC has a nuclear localization motif and localizes in the nucleus.
Function p30 DBC is an endogenous inhibitor of the class III protein deacetylase SIRT1. p30 DBC directly interacts with the catalytic domain of SIRT1 and inhibits the deacetylase activity of SIRT1. In doing so, p30 DBC promotes the acetylation of SIRT1 substrates such as p53 and FOXO3 following cellular stress in several cancer cell lines and inhibits SIRT1-dependent cell survival.
p30 DBC inhibits the activity of SUV39H1 methyltransferase and regulate heterochromatin formation via its inhibitory effect toward both SIRT1 and SUV39H1.
p30 DBC contains the Nudix hydrolase (MutT) domain, which is predicted to bind nucleoside diphosphate sugars and nicotinamide adenine dinucleotide (NAD), a co-substrate for SIRT1 enzyme. However, the Nudix domain of p30 DBC is predicted to be catalytically inactive.
In response to apoptosis-inducing signals, such as exposure to TNFalpha, etoposide or staurosporine, p30 DBC is cleaved into C-terminal p120 and p66 fragments in a caspase-dependent manner. The C-terminal fragment then relocalizes from nucleus to cytosol and mitochondria, and sensitizes cells to apoptotic stimuli. These findings suggest that p30 DBC promotes apoptosis through a positive feedback mechanism, which might suppress tumorigenesis by facilitating cell death in response to cellular stresses.
p30 DBC was found to act as a transcriptional coactivator of retinoic acid receptor alpha (RARalpha). The induction of RARalpha target genes such as Sox9 and HoxA1 gene in response to retinoic acid requires p30 DBC in MCF-7 breast cancer cells. This transcriptional activity of p30 DBC is not affected by SIRT1 inhibitor nicotinamide, suggesting that at least this transcriptional regulation function of p30 DBC is independent of SIRT1.
The first 150 amino acids of p30 DBC has been shown to interact with ERalpha through its hormone-binding domain in an estrogen-independent manner. The interaction between p30 DBC and ERalpha could stabilize ERalpha and promote breast cancer cell survival.
In addition to regulating ERalpha activity, p30 DBC could also act as an androgen receptor (AR) coactivator. The ligand binding domain (LBD) of AR interacts with the N-terminus of p30 DBC (residues 1~265) in the presence of AR ligand. This interaction enhances AR-DNA binding and facilitates AR's transcriptional activity. Knocking-down of p30 DBC decreases the induction of AR target genes including prostate specific antigen (PSA) in LNCaP prostate cancer cells.
Homology Homologs were found in mammals. No p30 DBC homologs was identified in lower organism so far.

Implicated in

Note
  
Entity Breast and prostate carcinomas
Note p30 DBC was initially identified to be downregulated in some breast and lung cancer specimens. However, in contrast to these findings, several microarray studies showed that p30 DBC mRNA is upregulated in breast cancers. In addition, p30 DBC1 could enhance ERalpha and AR signaling and promotes breast and prostate cancer cell proliferation. Therefore, p30 DBC gene could play a role in tumorigenesis based on in vitro studies, however, its function in cancer etiology remain to be verified in vivo.
Prognosis High expression of p30 DBC is associated with poor prognosis and metastasis of breast carcinoma.
  

Bibliography

Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of sirtuin domain deacetylases by NAD metabolites.
Anantharaman V, Aravind L.
Cell Cycle. 2008 May 15;7(10):1467-72. Epub 2008 Feb 29.
PMID 18418069
 
Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma.
Cha EJ, Noh SJ, Kwon KS, Kim CY, Park BH, Park HS, Lee H, Chung MJ, Kang MJ, Lee DG, Moon WS, Jang KY.
Clin Cancer Res. 2009 Jul 1;15(13):4453-9. Epub 2009 Jun 9.
PMID 19509139
 
HDAC3 is negatively regulated by the nuclear protein DBC1.
Chini CC, Escande C, Nin V, Chini EN.
J Biol Chem. 2010 Dec 24;285(52):40830-7. Epub 2010 Oct 28.
PMID 21030595
 
Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.
Escande C, Chini CC, Nin V, Dykhouse KM, Novak CM, Levine J, van Deursen J, Gores GJ, Chen J, Lou Z, Chini EN.
J Clin Invest. 2010 Feb 1;120(2):545-58. doi: 10.1172/JCI39319. Epub 2010 Jan 11.
PMID 20071779
 
Deleted in breast cancer 1, a novel androgen receptor (AR) coactivator that promotes AR DNA-binding activity.
Fu J, Jiang J, Li J, Wang S, Shi G, Feng Q, White E, Qin J, Wong J.
J Biol Chem. 2009 Mar 13;284(11):6832-40. Epub 2009 Jan 5.
PMID 19126541
 
Identification and characterization of a novel nuclear protein complex involved in nuclear hormone receptor-mediated gene regulation.
Garapaty S, Xu CF, Trojer P, Mahajan MA, Neubert TA, Samuels HH.
J Biol Chem. 2009 Mar 20;284(12):7542-52. Epub 2009 Jan 8.
PMID 19131338
 
DBC2, a candidate for a tumor suppressor gene involved in breast cancer.
Hamaguchi M, Meth JL, von Klitzing C, Wei W, Esposito D, Rodgers L, Walsh T, Welcsh P, King MC, Wigler MH.
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13647-52. Epub 2002 Oct 7.
PMID 12370419
 
Identification of DBC1 as a transcriptional repressor for BRCA1.
Hiraike H, Wada-Hiraike O, Nakagawa S, Koyama S, Miyamoto Y, Sone K, Tanikawa M, Tsuruga T, Nagasaka K, Matsumoto Y, Oda K, Shoji K, Fukuhara H, Saji S, Nakagawa K, Kato S, Yano T, Taketani Y.
Br J Cancer. 2010 Mar 16;102(6):1061-7. Epub 2010 Feb 16.
PMID 20160719
 
Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor {alpha} activity and co-activator synergy.
Ji Yu E, Kim SH, Heo K, Ou CY, Stallcup MR, Kim JH.
Nucleic Acids Res. 2011 May 19. [Epub ahead of print]
PMID 21596782
 
p30 DBC is a potential regulator of tumorigenesis.
Kim JE, Chen J, Lou Z.
Cell Cycle. 2009 Sep 15;8(18):2932-5. Epub 2009 Sep 8. (REVIEW)
PMID 19657230
 
Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.
Koch HB, Zhang R, Verdoodt B, Bailey A, Zhang CD, Yates JR 3rd, Menssen A, Hermeking H.
Cell Cycle. 2007 Jan 15;6(2):205-17. Epub 2007 Jan 20.
PMID 17314511
 
Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma.
Lee H, Kim KR, Noh SJ, Park HS, Kwon KS, Park BH, Jung SH, Youn HJ, Lee BK, Chung MJ, Koh DH, Moon WS, Jang KY.
Hum Pathol. 2011 Feb;42(2):204-13. Epub 2010 Nov 5.
PMID 21056897
 
Inhibition of SUV39H1 methyltransferase activity by DBC1.
Li Z, Chen L, Kabra N, Wang C, Fang J, Chen J.
J Biol Chem. 2009 Apr 17;284(16):10361-6. Epub 2009 Feb 13.
PMID 19218236
 
MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair.
Sharma GG, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N, Bhadra U, Pandita RK, Porteus MH, Chen DJ, Cote J, Pandita TK.
Mol Cell Biol. 2010 Jul;30(14):3582-95. Epub 2010 May 17.
PMID 20479123
 
Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling.
Sundararajan R, Chen G, Mukherjee C, White E.
Oncogene. 2005 Jul 21;24(31):4908-20.
PMID 15824730
 
Modulation of estrogen receptor alpha protein level and survival function by DBC-1.
Trauernicht AM, Kim SJ, Kim NH, Boyer TG.
Mol Endocrinol. 2007 Jul;21(7):1526-36. Epub 2007 May 1.
PMID 17473282
 
Negative regulation of the deacetylase SIRT1 by DBC1.
Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W.
Nature. 2008 Jan 31;451(7178):587-90.
PMID 18235502
 

Citation

This paper should be referenced as such :
Yuan, J ; Lou, Z
KIAA1967 (KIAA1967)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1038-1040.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KIAA1967ID46056ch8p21.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)CCAR2   23360
Cards
AtlasKIAA1967ID46056ch8p21
Entrez_Gene (NCBI)CCAR2  57805  cell cycle and apoptosis regulator 2
AliasesDBC-1; DBC1; KIAA1967; NET35; 
p30; p30DBC
GeneCards (Weizmann)CCAR2
Ensembl hg19 (Hinxton)ENSG00000158941 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000158941 [Gene_View]  chr8:22605026-22620470 [Contig_View]  CCAR2 [Vega]
ICGC DataPortalENSG00000158941
TCGA cBioPortalCCAR2
AceView (NCBI)CCAR2
Genatlas (Paris)CCAR2
WikiGenes57805
SOURCE (Princeton)CCAR2
Genetics Home Reference (NIH)CCAR2
Genomic and cartography
GoldenPath hg38 (UCSC)CCAR2  -     chr8:22605026-22620470 +  8p21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CCAR2  -     8p21.3   [Description]    (hg19-Feb_2009)
EnsemblCCAR2 - 8p21.3 [CytoView hg19]  CCAR2 - 8p21.3 [CytoView hg38]
Mapping of homologs : NCBICCAR2 [Mapview hg19]  CCAR2 [Mapview hg38]
OMIM607359   
Gene and transcription
Genbank (Entrez)AB075847 AF293335 AK022661 AK095712 AK096547
RefSeq transcript (Entrez)NM_021174 NM_199205
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CCAR2
Cluster EST : UnigeneHs.744848 [ NCBI ]
CGAP (NCI)Hs.744848
Alternative Splicing GalleryENSG00000158941
Gene ExpressionCCAR2 [ NCBI-GEO ]   CCAR2 [ EBI - ARRAY_EXPRESS ]   CCAR2 [ SEEK ]   CCAR2 [ MEM ]
Gene Expression Viewer (FireBrowse)CCAR2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57805
GTEX Portal (Tissue expression)CCAR2
Human Protein AtlasENSG00000158941-CCAR2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N163   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8N163  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8N163
Splice isoforms : SwissVarQ8N163
PhosPhoSitePlusQ8N163
Domains : Interpro (EBI)CCAR1/CCAR2    CCAR2    DBC1/CARP1_inactive_NUDIX_dom    EF-hand-dom_pair    S1-like_RNA-bd_dom   
Domain families : Pfam (Sanger)DBC1 (PF14443)    S1-like (PF14444)   
Domain families : Pfam (NCBI)pfam14443    pfam14444   
Domain families : Smart (EMBL)DBC1 (SM01122)  
Conserved Domain (NCBI)CCAR2
DMDM Disease mutations57805
Blocks (Seattle)CCAR2
SuperfamilyQ8N163
Human Protein Atlas [tissue]ENSG00000158941-CCAR2 [tissue]
Peptide AtlasQ8N163
HPRD09159
IPIIPI00182757   IPI00873406   IPI00941031   IPI00979738   IPI00978358   IPI00980303   IPI00982682   IPI00979880   IPI00982043   
Protein Interaction databases
DIP (DOE-UCLA)Q8N163
IntAct (EBI)Q8N163
FunCoupENSG00000158941
BioGRIDCCAR2
STRING (EMBL)CCAR2
ZODIACCCAR2
Ontologies - Pathways
QuickGOQ8N163
Ontology : AmiGOnuclear chromatin  RNA polymerase II core binding  RNA binding  enzyme inhibitor activity  enzyme inhibitor activity  protein binding  nucleus  nucleoplasm  nucleoplasm  spliceosomal complex  cytoplasm  mitochondrial matrix  transcription, DNA-templated  mRNA processing  cellular response to DNA damage stimulus  cell cycle  RNA splicing  response to UV  Wnt signaling pathway  enzyme binding  negative regulation of cell growth  regulation of protein stability  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  regulation of DNA-templated transcription, elongation  regulation of circadian rhythm  positive regulation of apoptotic process  negative regulation of catalytic activity  mitochondrial fragmentation involved in apoptotic process  DBIRD complex  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  rhythmic process  positive regulation of canonical Wnt signaling pathway  regulation of protein deacetylation  regulation of cellular response to heat  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage  positive regulation of DNA damage checkpoint  
Ontology : EGO-EBInuclear chromatin  RNA polymerase II core binding  RNA binding  enzyme inhibitor activity  enzyme inhibitor activity  protein binding  nucleus  nucleoplasm  nucleoplasm  spliceosomal complex  cytoplasm  mitochondrial matrix  transcription, DNA-templated  mRNA processing  cellular response to DNA damage stimulus  cell cycle  RNA splicing  response to UV  Wnt signaling pathway  enzyme binding  negative regulation of cell growth  regulation of protein stability  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  regulation of DNA-templated transcription, elongation  regulation of circadian rhythm  positive regulation of apoptotic process  negative regulation of catalytic activity  mitochondrial fragmentation involved in apoptotic process  DBIRD complex  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  rhythmic process  positive regulation of canonical Wnt signaling pathway  regulation of protein deacetylation  regulation of cellular response to heat  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage  positive regulation of DNA damage checkpoint  
REACTOMEQ8N163 [protein]
REACTOME PathwaysR-HSA-3371453 [pathway]   
NDEx NetworkCCAR2
Atlas of Cancer Signalling NetworkCCAR2
Wikipedia pathwaysCCAR2
Orthology - Evolution
OrthoDB57805
GeneTree (enSembl)ENSG00000158941
Phylogenetic Trees/Animal Genes : TreeFamCCAR2
HOVERGENQ8N163
HOGENOMQ8N163
Homologs : HomoloGeneCCAR2
Homology/Alignments : Family Browser (UCSC)CCAR2
Gene fusions - Rearrangements
Fusion : MitelmanC5/CCAR2 [9q33.2/8p21.3]  [t(9;9)(q33;q33)]  
Fusion : MitelmanCCAR2/FGFR2 [8p21.3/10q26.13]  [t(8;10)(p21;q26)]  
Fusion : MitelmanCCAR2/SORBS3 [8p21.3/8p21.3]  [t(8;8)(p21;p21)]  
Fusion : MitelmanFGFR2/CCAR2 [10q26.13/8p21.3]  [t(8;10)(p21;q26)]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCCAR2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CCAR2
dbVarCCAR2
ClinVarCCAR2
1000_GenomesCCAR2 
Exome Variant ServerCCAR2
ExAC (Exome Aggregation Consortium)ENSG00000158941
GNOMAD BrowserENSG00000158941
Genetic variants : HAPMAP57805
Genomic Variants (DGV)CCAR2 [DGVbeta]
DECIPHERCCAR2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCCAR2 
Mutations
ICGC Data PortalCCAR2 
TCGA Data PortalCCAR2 
Broad Tumor PortalCCAR2
OASIS PortalCCAR2 [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDCCAR2
BioMutasearch CCAR2
DgiDB (Drug Gene Interaction Database)CCAR2
DoCM (Curated mutations)CCAR2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CCAR2 (select a term)
intoGenCCAR2
NCG5 (London)CCAR2
Cancer3DCCAR2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607359   
Orphanet
MedgenCCAR2
Genetic Testing Registry CCAR2
NextProtQ8N163 [Medical]
TSGene57805
GENETestsCCAR2
Target ValidationCCAR2
Huge Navigator CCAR2 [HugePedia]
snp3D : Map Gene to Disease57805
BioCentury BCIQCCAR2
ClinGenCCAR2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD57805
Chemical/Pharm GKB GenePA134993792
Clinical trialCCAR2
Miscellaneous
canSAR (ICR)CCAR2 (select the gene name)
Probes
Litterature
PubMed118 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCCAR2
EVEXCCAR2
GoPubMedCCAR2
iHOPCCAR2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 12 16:25:26 CEST 2017

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.