Download Gene Section CARD8 (caspase recruitment domain family, member 8)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
CARD8 (caspase recruitment domain family,
member 8)
Frank A Kruyt
Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
Published in Atlas Database: May 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/CARD8ID913ch19q13.html
DOI: 10.4267/2042/16963
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
that contain the caspase-associated recruitment domain
(CARD) in their carboxy-termini that acts as a proteinprotein interaction interface. A 431 amino acids
CARD8 protein of 48-kDa (TUCAN-48) has been best
studied and more recently a 54-kDa isoform (TUCAN54, 487 amino acids) was identified sharing the same
CARD motif but with a different stretch of 80 aminoterminal residues. In the amino terminal part of the
protein a NAC/DEFCAP/CARD7 homology domain is
present.
Identity
Hugo: CARD8
Other
names:
CARDINAL;
DACAR;
DKFZp779L0366; KIAA0955; MGC57162; NDPP1;
TUCAN
Location: 19q13.32
DNA/RNA
Description
Expression
The CARD8 gene contains 13 exons spanning over
approximately 30 kb of genomic DNA.
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.
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/CARD8-48kDa, respectively.
Protein
Description
The CARD8 gene encodes different CARD8 isoforms
Schematic representation of two CARD8 variants. The CARD domain, the NAC/DEFCAP/CARD7 homology domain, and the aminoterminal residues that differ between the isoforms are indicated.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
294
CARD8 (caspase recruitment domain family, member 8)
Kruyt FA
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.
Implicated in
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.
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.
Non-small cell lung cancer (NSCLC)
Function
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.
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 CARDdependent 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.
Inflammatory bowel disease (IBD)
Disease
Crohn’s disease and ulcerative colitis.
Prognosis
Patients with IBD (Crohn’s 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.
References
Bouchier-Hayes L, Conroy H, Egan H, Adrain C, Creagh EM,
MacFarlane M, Martin SJ. CARDINAL, a novel caspase
recruitment domain protein, is an inhibitor of multiple NF-kappa
B activation pathways. J Biol Chem 2001;276:44069-44077.
Homology
CARD family proteins.
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. TUCAN, an antiapoptotic caspaseassociated recruitment domain family protein overexpressed in
cancer. J Biol Chem 2001;276:32220-32229.
Mutations
Somatic
Ten single nucleotide polymorphisms (SNPs) across
TUCAN/CARD8 have been identified in healthy
persons and patients suffering from inflammatory bowl
disease.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
Bouchier-Hayes L, Martin SJ. CARD games in apoptosis and
immunity. EMBO Rep 2002;3:616-621. (Review).
Stilo R, Leonardi A, Formisano L, Di Jeso B, Vito P, Liguoro D.
TUCAN /CARDINAL and DRAL participate in a common
pathway for modulation of NF-kappaB activation. FEBS Lett
2002;521:165-179.
295
CARD8 (caspase recruitment domain family, member 8)
Kruyt FA
Zhang H, Fu W. NDPP1 is a novel CARD domain containing
protein which can inhibit apoptosis and suppress NF-kB
activation. Int J Oncol 2002;20:1035-1040.
McGovern DP, Butler H, Ahmad T, Paolucci M, van Heel DA,
Negoro K, Hysi P, Ragoussis J, Travis SP, Cardon LR, Jewell
DP. TUCAN (CARD8) genetic variants and inflammatory bowel
disease. Gastroenterology 2006;131:1190-1196.
Razmara M, Srinivasula SM, Wang L, Poyet JL, Geddes,
DiStefano PS, Bertin J, Alnemri ES. CARD-8 protein, a new
CARD family member that regulates caspase-1 activation and
apoptosis. J Biol Chem 2003;277:13952-13968.
Fisher SA, Mirza MM, Onnie CM, Soars D, Lewis CM, Prescott
NJ, Mathew CG, Sanderson J, Forbes A, Todhunter C,
Donaldson P, Mansfield J. Combined Evidence From Three
Large British Association Studies Rejects TUCAN/CARD8 as
an IBD Susceptibility Gene. Gastroenterology 2007;132:20782080.
Damiano JS, Reed JC. CARD proteins as therapeutic targets
in cancer. Curr Drug Targets 2004;5:367-374. (Review).
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. A novel isoform
of TUCAN is overexpressed in human cancer tissues and
suppresses both caspase-8- and caspase-9-mediated
apoptosis. Cancer Res 2005;65:8706-8714.
Franke A, Rosenstiel P, Balschun T, Von Kampen O,
Schreiber S, Sina C, Hampe J, Karlsen TH, Vatn MH; The
IBSEN Study Group; Solberg C. No Association Between the
TUCAN (CARD8) Cys10Stop Mutation and Inflammatory
Bowel Disease in a Large Retrospective German and a
Clinically
Well-Characterized
Norwegian
Sample.
Gastroenterology 2007;132:2080.
Checinska A, Giaccone G, Hoogeland BS, Ferreira CG,
Rodriguez JA, Kruyt FA. TUCAN/CARDINAL/CARD8 and
apoptosis resistance in non-small cell lung cancer cells. BMC
Cancer 2006;6:166.
This article should be referenced as such:
Kruyt FA. CARD8 (caspase recruitment domain family,
member 8). Atlas Genet Cytogenet Oncol Haematol.2007;
11(4):294-296.
Checinska A, Oudejans JJ, Span SW, Rodriguez JA, Kruyt FA,
Giaccone G. The expression of TUCAN, an inhibitor of
apoptosis protein, in patients with advanced non-small cell lung
cancer treated with chemotherapy. Anticancer Res
2006;26:3819-3824.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
296