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CARD8 (caspase recruitment domain family, member 8)

Identity

Other namesCARDINAL
DACAR
DKFZp779L0366
KIAA0955
MGC57162
NDPP1
TUCAN
HGNC (Hugo) CARD8
LocusID (NCBI) 22900
Location 19q13.33
Location_base_pair Starts at 48711343 and ends at 48744320 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The CARD8 gene contains 13 exons spanning over approximately 30 kb of genomic DNA
Transcription At least 5 transcripts have been identified generated by alternative splicing that together with different start codon usage yield different CARD8 isoforms. Gene products encoded by exons 1 to 13 and 5 to 13 yield TUCAN/CARD8-54-kDa and TUCAN/CARD8-48-kDa, respectively.

Protein

 
  Schematic representation of two CARD8 variants. The CARD domain, the NAC/DEFCAP/CARD7 homology domain, and the amino-terminal residues that differ between the isoforms are indicated.
Description The CARD8 gene encodes different CARD8 isoforms that contain the caspase-associated recruitment domain (CARD) in their carboxy-termini that acts as a protein-protein interaction interface. A 431 amino acids CARD8 protein of 48-kDa (TUCAN-48) has been best studied and more recently a 54-kDa isoform (TUCAN-54, 487 amino acids) was identified sharing the same CARD motif but with a different stretch of 80 amino-terminal residues. In the amino terminal part of the protein a NAC/DEFCAP/CARD7 homology domain is present.
Expression Normal tissue: wide and differential expression at mRNA level in tissues; present in heart, brain, lung, muscle, spleen, ovary; high in kidney, testis and spinal cord; absent in liver.
Cancer: the CARD8 (48 kDa) protein is differentially expressed in cancer. High levels of CARD8 expression were found in tumor cell lines, including breast, prostate, ovarian and colon cancer cells as well as high expression in non-small cell lung cancer (NSCLC) cells and with hardly detectable expression in normal lung, in contrast to a lack of expression in small-cell lung cancer cell lines. In tumor specimens from patients CARD8 expression has been demonstrated in colon cancer and non-small cell lung cancer. The 54-kDa CARD8 isoform has a different expression profile when compared to TUCAN/CARD8-48. For example a number of breast cancer cell lines do not express TUCAN/CARD8-54, although some of them express TUCAN/CARD8-48. Expression also varies widely among different tumor cell lines with high levels in colon cancer cells.
Localisation In MCF-7 cells overexpressed CARD8 localized to both the cytoplasmic and nuclear compartment. In specimens derived from colon cancer cells a predominant cytoplasmic expression was found, whereas in NSCLC tumor samples CARD8 was either exclusively nuclear or cytoplasmic or present in both compartments.
Function CARD8 belongs to the CARD family of proteins that play a role in apoptosis regulation and NF-kB signaling associated with the innate or adaptive immune response. For example the binding of CARDs present in caspase-9 and Apaf-1 mediate the assembly of the apoptosome in which caspase-9 is activated. CARD motifs have different binding selectivity towards each other and the presence of additional structural/ functional domains in the various CARD-containing proteins may also determine the choice of interaction partner.
In literature there is some controversy on the function of CARD8. Some reports mention an apoptosis inhibitory function of CARD8 involving its CARD-dependent binding to procaspase-9, whereas others did not find an association between CARD8 and caspase-9 and instead found either pro-apoptotic activity of CARD8 and associations with the inflammatory caspase-1 or the regulatory subunit of IkB kinase (NEMO) thereby suppressing NF-kB activation. Also an interaction between the p53-responsive gene DRAL (FLH2) and CARD8 has been reported resulting in the suppression of NF-kB activation. Furthermore, TUCAN/CARD8-54 was found to inhibit chemotherapy-induced caspase-9 activation and Fas ligand-induced caspase-8 activation. Based mainly on its proposed anti-apoptotic activity CARD8 is considered as a possible therapeutic target for cancer.
Homology CARD family proteins.

Mutations

Somatic Ten single nucleotide polymorphisms (SNPs) across TUCAN/CARD8 have been identified in healthy persons and patients suffering from inflammatory bowl disease.

Implicated in

Entity Colon cancer
Prognosis TUCAN/CARD8 expression has been analyzed by immunohistochemistry in paraffin-embedded colon cancer specimens (N=102) derived from patients with clinical stage II that were surgically treated. TUCAN/CARD8 staining was stronger in colon cancer cells when compared to normal cells in 64% of the 102 specimens examined. Scoring staining intensity revealed a significant correlation between high TUCAN/CARD8 expression in tumor cells and shorter patient survival.
  
Entity Non-small cell lung cancer (NSCLC)
Prognosis The expression of TUCAN/CARD8 has been determined by immunohistochemistry in tumor specimens derived from NSCLC patients (N=49, stage III and IV) that received neoadjuvant or palliative chemotherapy. TUCAN/CARD8 expression was detected in 69% of the samples, showing exclusively cytoplasmic (27%) or nuclear (11%) staining, or in both compartments (31%). No correlation between response to chemotherapy or expression/ localization was found, although, cytoplasm-only staining NSCLC samples predicted shorter survival, suggesting a possible prognostic value.
  
Entity Inflammatory bowel disease (IBD)
Disease Crohnıs disease and ulcerative colitis
Prognosis Patients with IBD (Crohnıs disease (CD) and ulcerative colitis) and healthy individuals were genotyped for SNP. A significant association between a TUCAN SNP and CD was found. However, in other reports this association was not confirmed, rejecting TUCAN/CARD8 as a possible susceptibility gene for IBD.
  

External links

Nomenclature
HGNC (Hugo)CARD8   17057
Cards
AtlasCARD8ID913ch19q13
Entrez_Gene (NCBI)CARD8  22900  caspase recruitment domain family, member 8
GeneCards (Weizmann)CARD8
Ensembl hg19 (Hinxton)ENSG00000105483 [Gene_View]  chr19:48711343-48744320 [Contig_View]  CARD8 [Vega]
Ensembl hg38 (Hinxton)ENSG00000105483 [Gene_View]  chr19:48711343-48744320 [Contig_View]  CARD8 [Vega]
ICGC DataPortalENSG00000105483
cBioPortalCARD8
AceView (NCBI)CARD8
Genatlas (Paris)CARD8
WikiGenes22900
SOURCE (Princeton)CARD8
Genomic and cartography
GoldenPath hg19 (UCSC)CARD8  -     chr19:48711343-48744320 -  19q13.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CARD8  -     19q13.33   [Description]    (hg38-Dec_2013)
EnsemblCARD8 - 19q13.33 [CytoView hg19]  CARD8 - 19q13.33 [CytoView hg38]
Mapping of homologs : NCBICARD8 [Mapview hg19]  CARD8 [Mapview hg38]
OMIM609051   
Gene and transcription
Genbank (Entrez)AB023172 AF143869 AF322184 AF331519 AF405558
RefSeq transcript (Entrez)NM_001184900 NM_001184901 NM_001184902 NM_001184903 NM_001184904 NM_014959
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_029574 NT_011109 NW_001838497 NW_004929415
Consensus coding sequences : CCDS (NCBI)CARD8
Cluster EST : UnigeneHs.655940 [ NCBI ]
CGAP (NCI)Hs.655940
Alternative Splicing : Fast-db (Paris)GSHG0033346
Alternative Splicing GalleryENSG00000105483
Gene ExpressionCARD8 [ NCBI-GEO ]     CARD8 [ SEEK ]   CARD8 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y2G2 (Uniprot)
NextProtQ9Y2G2  [Medical]
With graphics : InterProQ9Y2G2
Splice isoforms : SwissVarQ9Y2G2 (Swissvar)
Domaine pattern : Prosite (Expaxy)CARD (PS50209)   
Domains : Interpro (EBI)CARD    DEATH-like_dom    FIIND_dom   
Related proteins : CluSTrQ9Y2G2
Domain families : Pfam (Sanger)CARD (PF00619)    FIIND (PF13553)   
Domain families : Pfam (NCBI)pfam00619    pfam13553   
Domain families : Smart (EMBL)CARD (SM00114)  
DMDM Disease mutations22900
Blocks (Seattle)Q9Y2G2
PDB (SRS)4IKM   
PDB (PDBSum)4IKM   
PDB (IMB)4IKM   
PDB (RSDB)4IKM   
Human Protein AtlasENSG00000105483
Peptide AtlasQ9Y2G2
HPRD16425
IPIIPI00218145   IPI00942890   IPI00032131   IPI00922017   IPI00425928   IPI00984191   IPI00974394   IPI00973940   IPI00977493   IPI00974376   IPI00974558   IPI00642708   IPI00978124   IPI00978440   IPI00977620   IPI00976952   IPI00980389   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y2G2
IntAct (EBI)Q9Y2G2
FunCoupENSG00000105483
BioGRIDCARD8
IntegromeDBCARD8
STRING (EMBL)CARD8
Ontologies - Pathways
QuickGOQ9Y2G2
Ontology : AmiGOprotein binding  nucleus  nucleolus  cytoplasm  activation of cysteine-type endopeptidase activity involved in apoptotic process  cysteine-type endopeptidase activator activity involved in apoptotic process  NACHT domain binding  protein homodimerization activity  negative regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  positive regulation of interleukin-1 beta secretion  NLRP3 inflammasome complex  
Ontology : EGO-EBIprotein binding  nucleus  nucleolus  cytoplasm  activation of cysteine-type endopeptidase activity involved in apoptotic process  cysteine-type endopeptidase activator activity involved in apoptotic process  NACHT domain binding  protein homodimerization activity  negative regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  positive regulation of interleukin-1 beta secretion  NLRP3 inflammasome complex  
Pathways : KEGGNOD-like receptor signaling pathway   
Protein Interaction DatabaseCARD8
DoCM (Curated mutations)CARD8
Wikipedia pathwaysCARD8
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerCARD8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CARD8
dbVarCARD8
ClinVarCARD8
1000_GenomesCARD8 
Exome Variant ServerCARD8
SNP (GeneSNP Utah)CARD8
SNP : HGBaseCARD8
Genetic variants : HAPMAPCARD8
Genomic VariantsCARD8  CARD8 [DGVbeta]
Mutations
ICGC Data PortalENSG00000105483 
Somatic Mutations in Cancer : COSMICCARD8 
CONAN: Copy Number AnalysisCARD8 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)19:48711343-48744320
Mutations and Diseases : HGMDCARD8
OMIM609051   
MedgenCARD8
NextProtQ9Y2G2 [Medical]
GENETestsCARD8
Disease Genetic AssociationCARD8
Huge Navigator CARD8 [HugePedia]  CARD8 [HugeCancerGEM]
snp3D : Map Gene to Disease22900
DGIdb (Drug Gene Interaction db)CARD8
General knowledge
Homologs : HomoloGeneCARD8
Homology/Alignments : Family Browser (UCSC)CARD8
Phylogenetic Trees/Animal Genes : TreeFamCARD8
Chemical/Protein Interactions : CTD22900
Chemical/Pharm GKB GenePA134916154
Clinical trialCARD8
Cancer Resource (Charite)ENSG00000105483
Other databases
Probes
Litterature
PubMed51 Pubmed reference(s) in Entrez
CoreMineCARD8
GoPubMedCARD8
iHOPCARD8

Bibliography

CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways.
Bouchier-Hayes L, Conroy H, Egan H, Adrain C, Creagh EM, MacFarlane M, Martin SJ
The Journal of biological chemistry. 2001 ; 276 (47) : 44069-44077.
PMID 11551959
 
TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer.
Pathan N, Marusawa H, Krajewska M, Matsuzawa S, Kim H, Okada K, Torii S, Kitada S, Krajewski S, Welsh K, Pio F, Godzik A, Reed JC
The Journal of biological chemistry. 2001 ; 276 (34) : 32220-32229.
PMID 11408476
 
CARD games in apoptosis and immunity.
Bouchier-Hayes L, Martin SJ
EMBO reports. 2002 ; 3 (7) : 616-621.
PMID 12101092
 
TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of NF-kappaB activation.
Stilo R, Leonardi A, Formisano L, Di Jeso B, Vito P, Liguoro D
FEBS letters. 2002 ; 521 (1-3) : 165-169.
PMID 12067710
 
NDPP1 is a novel CARD domain containing protein which can inhibit apoptosis and suppress NF-kappaB activation.
Zhang H, Fu W
International journal of oncology. 2002 ; 20 (5) : 1035-1040.
PMID 11956601
 
CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis.
Razmara M, Srinivasula SM, Wang L, Poyet JL, Geddes BJ, DiStefano PS, Bertin J, Alnemri ES
The Journal of biological chemistry. 2002 ; 277 (16) : 13952-13958.
PMID 11821383
 
CARD proteins as therapeutic targets in cancer.
Damiano JS, Reed JC
Current drug targets. 2004 ; 5 (4) : 367-374.
PMID 15134219
 
A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis.
Yamamoto M, Torigoe T, Kamiguchi K, Hirohashi Y, Nakanishi K, Nabeta C, Asanuma H, Tsuruma T, Sato T, Hata F, Ohmura T, Yamaguchi K, Kurotaki T, Hirata K, Sato N
Cancer research. 2005 ; 65 (19) : 8706-8714.
PMID 16204039
 
TUCAN/CARDINAL/CARD8 and apoptosis resistance in non-small cell lung cancer cells.
Checinska A, Giaccone G, Hoogeland BS, Ferreira CG, Rodriguez JA, Kruyt FA
BMC cancer. 2006 ; 6 : page 166.
PMID 16796750
 
The expression of TUCAN, an inhibitor of apoptosis protein, in patients with advanced non-small cell lung cancer treated with chemotherapy.
Checinska A, Oudejans JJ, Span SW, Rodriguez JA, Kruyt FA, Giaccone G
Anticancer research. 2006 ; 26 (5B) : 3819-3824.
PMID 17094407
 
TUCAN (CARD8) genetic variants and inflammatory bowel disease.
McGovern DP, Butler H, Ahmad T, Paolucci M, van Heel DA, Negoro K, Hysi P, Ragoussis J, Travis SP, Cardon LR, Jewell DP
Gastroenterology. 2006 ; 131 (4) : 1190-1196.
PMID 17030188
 
Combined evidence from three large British Association studies rejects TUCAN/CARD8 as an IBD susceptibility gene.
Fisher SA, Mirza MM, Onnie CM, Soars D, Lewis CM, Prescott NJ, Mathew CG, Sanderson J, Forbes A, Todhunter C, Donaldson P, Mansfield J
Gastroenterology. 2007 ; 132 (5) : 2078-2080.
PMID 17484911
 
Combined evidence from three large British Association studies rejects TUCAN/CARD8 as an IBD susceptibility gene.
Fisher SA, Mirza MM, Onnie CM, Soars D, Lewis CM, Prescott NJ, Mathew CG, Sanderson J, Forbes A, Todhunter C, Donaldson P, Mansfield J
Gastroenterology. 2007 ; 132 (5) : 2078-2080.
PMID 17484911
 
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Contributor(s)

Written05-2007Frank A. Kruyt

Citation

This paper should be referenced as such :
Kruyt FA
CARD8 (caspase recruitment domain family, member 8);
Atlas Genet Cytogenet Oncol Haematol. May 2007
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CARD8ID913ch19q13.html

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indexed on : Sun Dec 21 02:54:30 CET 2014

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