Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   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

CASP8 (Caspase 8, Apoptosis-Related Cysteine Peptidase)

Written2013-11Selcen Öztürk, Kolja Schleich, Inna N Lavrik
Division of Immunogenetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany (SO, KS, INL); Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany (INL)

(Note : for Links provided by Atlas : click)

Identity

Other namesALPS2B
CAP4
Casp-8
FLICE
MACH
MCH5
HGNC (Hugo) CASP8
LocusID (NCBI) 841
Atlas_Id 925
Location 2q33.1  [Link to chromosome band 2q33]
Location_base_pair Starts at 202098166 and ends at 202152434 bp from pter ( according to hg19-Feb_2009)  [Mapping CASP8.png]
Local_order CASP8 is located on chromosome 2 on the long arm (positive strand), and lies between the CASP10 and STRADB genes.
 
  Chromosomal location of CASP8 and nearby genes
Fusion genes
(updated 2016)
ACVR2A (2q22.3) / CASP8 (2q33.1)CASP8 (2q33.1) / ALS2CR12 (2q33.1)CASP8 (2q33.1) / PCGF5 (10q23.32)
CASP8 (2q33.1) / UBR3 (2q31.1)RPS6 (9p22.1) / CASP8 (2q33.1)

DNA/RNA

 
  Schematic representation of the structure of the 54kb CASP8 gene, which contains 10 exons and can be transcribed into 6 alternative splice variants.
Description 54269 bases with 11 exons.
Transcription There are 6 transcriptional variants of CASP8 and they are described in Table 1.

Protein

Note Caspases are a family of cysteinyl aspartate specific proteases which are synthesized as zymogens. Caspase-8 was discovered as a component of the CD95 (Fas/APO-1) death-inducing signaling complex (DISC) (Muzio et al., 1996).
 
  Involvement of procaspase-8 in death-receptor signaling. (A) Procaspase-8 is recruited to the CD95 or TRAIL DISC through the adaptor protein FADD. Upon activation of TNF, procaspase-8 is recruited through FADD and TRADD. For activation, procaspase-8 requires dimerization and internal cleavage. The major function of procaspase-8 in DR signaling is induction of apoptosis, but it also regulates necroptosis or NF-kB via RIP1/RIP3 and c-FLIP(L). (B) Procaspase-8 consists of a prodomain harboring tandem death effector domains (DED) followed by one large (p18) and one small (p10) catalytic subunit. Cleavage between p18 and p10 generates the intermediate p43/p41 which is further processed to the fully active form by cleavage between the prodomain and p18.
Description Caspase-8 has a number of isoforms, including procaspase-8a (496 aa), procaspase-8b (479 aa), procaspase-8c (464 aa), procaspase-8e (235 aa), procaspase-8g or caspase-8L (538 aa) and caspase-8 short (108 aa).
Only two isoforms are predominantly expressed in many different tissues and cell lines: procaspase-8a and procaspase-8b (Scaffidi et al., 1997). They act as the main initiator caspases in death receptor-induced apoptosis.
Caspase-8L was reported to be expressed in human peripheral blood lymphocytes as a truncated protein, which lacks the C-terminal protease domain (Horiuchi et al., 2000). Therefore, it is suggested that caspase-8L is recruited into the DISC but remains proteolytically inert, interfering with the transduction of the signal from the DISC (Himeji et al., 2002).
An isoform that is detected in bone marrow mononuclear cells is named caspase-8 short. Although it only contains the first DED and a part of the second DED, overexpression of caspase-8 short is reported to increase sensitivity to apoptosis (Xu et al., 2009).
In addition to caspase-8 isoforms, there is a number of cleavage products described, which are formed in the course of apoptosis. Apoptotic processing of procaspase-8a/b involves generation of the cleavage products p43/p41, p30, the prodomains p26/p24, p18 and p10 (Hoffmann et al., 2009). The latter two cleavage products form the active caspase-8 heterotetramer p102-p182 that triggers apoptosis (Lavrik and Krammer, 2012).
Expression Caspase-8 is expressed in almost all kind of tissues, with the highest expression in the immune system and lowest in the nervous system (McCall et al., 2011).
Localisation Procaspase-8 mainly localizes to the cytosol, in close proximity to the membrane (Medema et al., 1997). It may also localize to mitochondria (Qin et al., 2001, Chandra et al., 2004) or centrosomes (Mielgo et al., 2009). Caspase-8 cleavage products are reported to localize to the nucleus as well as the cytosol (Benchoua et al., 2002, Yao et al., 2007).
Function Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Upon stimulation, procaspase-8 is recruited to the CD95 or TRAIL DISC, or TNF complex II. Procaspase-8 activation involves dimerization, oligomerization and cleavage (Schleich et al., 2012). The cleavage of procaspase-8 involves several steps, leading to the generation of the active caspase-8 heterotetramer p102-p182 (Lavrik and Krammer, 2012). Depending on the cell type, active caspase-8 either directly cleaves effector caspases (caspase-3 and caspase-7) or cleaves Bid, which eventually leads to release of cytochrome C and apoptosome formation followed by cleavage of effector caspase-3, caspase-6 and caspase-7 by procaspase-9 (Scaffidi et al., 1998; Scaffidi et al., 1999).
In addition to apoptosis, caspase-8 has a role in programmed necrosis (necroptosis) as well. Caspase-8 can be recruited to the necroptotic complexes (necrosome or ripoptosome) together with RIP1, RIP3 and FADD. It would then cleave RIP1 and RIP3, and therefore block necroptosis (Stupack et al., 2006, Feoktistova et al., 2011; Tenev et al., 2011).
Caspase-8 also has an essential role for NF-kB signaling via many different stimuli including CD95, TRAIL, TCR and TLR stimulations (Kataoka and Tschopp, 2004; Dohrman et al., 2005; Su et al., 2005; Lemmers et al., 2007; Grunert et al., 2012). Interestingly, although the activation of procaspase-8 to p102-p182 heterotetramer is necessary for MAPK signaling (Kober et al., 2011), it is not necessary for NF-kB signaling upon CD95 stimulation (Neumann et al., 2010).
Caspase-8 has been also reported to affect metastasis. Interestingly, although loss of caspase-8 potentiates metastasis, under conditions where apoptosis is compromised, caspase-8 can promote tumor cell migration and metastasis (Stupack et al., 2006, Barbero et al., 2009).
Homology Caspase-10, FADD, c-FLIP.

Mutations

Germinal A homozygous C to T mutation at residue 248 leads to familial autoimmune lymphoproliferative syndrome type 2B.
Somatic Various somatic mutations of CASP8 are identified in different carcinomas. Mutations are observed at different parts of caspase-8, but they all lead to a catalytically inactive form.
- Hepatocellular carcinoma: CASP8 is frequently inactivated by the frameshift somatic mutation 1225-1226delTG in hepatocellular carcinomas, resulting in a premature termination of amino-acid synthesis in the p10 protease subunit (Soung et al., 2005b).
- Gastric carcinoma: Inactivating CASP8 mutations are detected at different sites in about 10% of advanced gastric carcinomas (Soung et al., 2005a).
- Colorectal carcinoma: Inactivating CASP8 mutations are detected at different sites in about 5% of invasive colorectal carcinomas (Kim et al., 2003).
- Vulvar squamous carcinoma: Deletion of leucine 62 (ΔLeu62casp-8) is detected in A431 human vulvar squamous carcinoma cells. ΔLeu62casp-8 has a shorter half-life than wild-type caspase-8 and cannot interact with caspase-8 or FADD; therefore lost its proapoptotic activity (Liu et al., 2002).
- Head and neck carcinoma: A mutation was detected in the tumor cells from head and neck carcinoma that modifies the stop codon and lengthening the protein by 88 amino acids (Mandruzzato et al., 1997).
- Neuroblastoma : An Alanine to Valine missense mutation was detected at codon 96 in a neuroblastoma sample which lacks CASP8 mRNA expression (Takita et al., 2001).

Implicated in

Note
Entity Hepatocellular carcinoma
Disease Hepatocellular carcinoma accounts for the majority of liver cancers. Mostly, it is secondary to cirrhosis, which is caused mainly by alcohol abuse or hepatitis B/C infections. A somatic mutation in CASP8 leading to deletion of the bases 1225-1226 was detected in 9 out of 69 hepatocellular carcinoma samples from unrelated patients. This deletion results in a frameshift and therefore premature termination of amino-acid synthesis in the p10 protease subunit, consequently inactivating caspase-8 (Soung et al., 2005b).
  
Entity Gastric carcinoma
Disease Gastric carcinomas arise from the epithelium of the stomach. In a study by Soung and colleagues (Soung et al., 2005a), 122 advanced gastric carcinoma samples were analyzed for mutations in the coding region and the exon-intron junctions of CASP8 gene by PCR-SSCP analysis. In 13 samples, mutations in caspase-8 were found. All mutants were still expressed at a similar level compared to wild-type caspase-8, however, when transfected into cell lines, all mutants except one showed defects in apoptosis.
  
Entity Colorectal carcinoma
Disease Colorectal cancer arises from colon, rectum or appendix. In the analysis of 82 colorectal adenomas and 98 invasive colorectal carcinomas, 5 mutations were detected only in the colorectal carcinomas but not in the adenomas. 3 out of 5 of these mutations acted in a dominant negative manner and suppressed apoptosis (Kim et al., 2003).
  
Entity Vulvar squamous carcinoma
Disease In the analysis of A431 human vulvar squamous carcinoma cells, a mutation in CASP8 leading to deletion of leucine 62 was detected. This mutant version of caspase-8 retained its enzymatic activity, however, it lost the ability to interact with itself, wild-type caspase-8 or FADD and therefore lost its proapoptotic activity (Liu et al., 2002).
  
Entity Head and neck carcinoma
Disease Head and neck carcinomas start in the lip, oral cavity, nasal cavity, paranasal sinuses, pharynx, or larynx and the majority (90%) originates from the epithelium, therefore named squamous cell carcinomas. A mutation in CASP8 was detected in the cells from a tumor relapse resected from the oral cavity of a late-stage squamous cell carcinoma patient. This mutation was found to modify the stop codon and add an Alu repeat to the coding region. Therefore, the mutant protein is 88 amino acids longer than the wild type and cannot efficiently act as an apoptotic protein (Mandruzzato et al., 1997).
  
Entity Neuroblastoma
Disease Neuroblastoma arises from immature nerve cells. It is mainly localized to adrenal medulla. In a study where human neuroblastoma cells were transferred to chick chorioallantoic membrane, tumor development was monitored. Although presence or lack of caspase-8 did not change primary tumor growth, metastasis was highly promoted in the tumors lacking caspase-8 due to impaired programmed cell death (Stupack et al., 2006). In a similar study, tumor cells additionally lacking caspase-3 were used to test non-apoptotic effects of caspase-8 on neuroblastoma metastasis. Interestingly, tumors lacking only caspase-3 metastasized more efficiently than tumors lacking both caspases, pointing out that caspase-8 also shows non-apoptotic properties such as enhancing cell migration (Barbero et al., 2009).
Silencing of caspase-8 was also observed in human neuroblastoma samples. In two studies by Takita and colleagues, 11 out of 15 and 19 out of 27 neuroblastoma samples did not express caspase-8, detected by real-time PCR (Takita et al., 2000; Takita et al., 2001). Furthermore, a missense mutation was detected at codon 96 in one of the samples lacking caspase-8 expression (Takita et al., 2000).
Furthermore, silencing of CASP8 in neuroblastoma was found to be associated with MYCN amplification. 10 out of 16 patients with MYCN amplification had completely methylated CASP8 alleles opposed to only 1 out of 26 patients without MYCN amplification. Interestingly, one patient among these 42 patients had a deletion of the CASP8 gene (Teitz et al., 2000).
  
Entity Medulloblastoma
Disease Medulloblastoma is a tumor of the brain that originates in the cerebellum or posterior fossa. In one study of medulloblastoma, 14 out of 27 tumors were identified to have lost CASP8 mRNA expression (Zuzak et al., 2002). Furthermore, another study showed that CASP8 expression was reversely correlating with the disease. The 5-year cumulative progression-free survival rate of the patients with weak CASP8 expression was 31%, and with moderate/strong caspase-8 expression 73% (Pingoud-Meier et al., 2003).
  
Entity Small cell lung carcinoma
Disease Small cell lung carcinomas commonly originate from the lung, although rarely can originate also from cervix, prostate or gastrointesinal tract. In this carcinoma, tumor cells are much smaller than normal cells with almost no cytoplasm. In one study, 13 out of 25 small cell lung carcinoma samples showed silencing of CASP8 due to methylation (Hopkins-Donaldson et al., 2003).
  
Entity Autoimmune lymphoproliferative syndrome type 2B
Disease A homozygous C to T mutation in caspase-8 at residue 248 in the p18 protease subunit leads to autoimmune lymphoproliferative syndrome type 2B (Chun et al., 2002).
Autoimmune Lymphoproliferative Syndrome Type 2B is an autosomal dominant disease where there are defects in activation of T cells, B cells, and natural killer cells of the patients as well as in CD95-mediated apoptosis. Patients have lymphoproliferation and thus lymphadenopathy, splenomegaly and autoimmunity.
  

Bibliography

Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis.
Barbero S, Mielgo A, Torres V, Teitz T, Shields DJ, Mikolon D, Bogyo M, Barila D, Lahti JM, Schlaepfer D, Stupack DG.
Cancer Res. 2009 May 1;69(9):3755-63. doi: 10.1158/0008-5472.CAN-08-3937. Epub 2009 Apr 21.
PMID 19383910
 
Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2.
Benchoua A, Couriaud C, Guegan C, Tartier L, Couvert P, Friocourt G, Chelly J, Menissier-de Murcia J, Onteniente B.
J Biol Chem. 2002 Sep 13;277(37):34217-22. Epub 2002 Jun 13.
PMID 12065591
 
Association of active caspase 8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death.
Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG.
Mol Cell Biol. 2004 Aug;24(15):6592-607.
PMID 15254227
 
Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.
Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ.
Nature. 2002 Sep 26;419(6905):395-9.
PMID 12353035
 
Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-kappa B activation.
Dohrman A, Kataoka T, Cuenin S, Russell JQ, Tschopp J, Budd RC.
J Immunol. 2005 May 1;174(9):5270-8.
PMID 15843523
 
cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.
Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Hacker G, Leverkus M.
Mol Cell. 2011 Aug 5;43(3):449-63. doi: 10.1016/j.molcel.2011.06.011. Epub 2011 Jul 7.
PMID 21737330
 
The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-kB by TRAIL.
Grunert M, Gottschalk K, Kapahnke J, Gundisch S, Kieser A, Jeremias I.
Cell Death Dis. 2012 Oct 25;3:e414. doi: 10.1038/cddis.2012.154.
PMID 23096115
 
Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade.
Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M.
Blood. 2002 Jun 1;99(11):4070-8.
PMID 12010809
 
A new C-terminal cleavage product of procaspase-8, p30, defines an alternative pathway of procaspase-8 activation.
Hoffmann JC, Pappa A, Krammer PH, Lavrik IN.
Mol Cell Biol. 2009 Aug;29(16):4431-40. doi: 10.1128/MCB.02261-07. Epub 2009 Jun 15.
PMID 19528225
 
Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation.
Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D, Ludwig C, Zangemeister-Wittke U, Stahel R.
Cell Death Differ. 2003 Mar;10(3):356-64.
PMID 12700635
 
Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes.
Horiuchi T, Himeji D, Tsukamoto H, Harashima S, Hashimura C, Hayashi K.
Biochem Biophys Res Commun. 2000 Jun 16;272(3):877-81.
PMID 10860845
 
N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway.
Kataoka T, Tschopp J.
Mol Cell Biol. 2004 Apr;24(7):2627-36.
PMID 15024054
 
Inactivating mutations of caspase-8 gene in colorectal carcinomas.
Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH.
Gastroenterology. 2003 Sep;125(3):708-15.
PMID 12949717
 
Caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation.
Kober AM, Legewie S, Pforr C, Fricker N, Eils R, Krammer PH, Lavrik IN.
Cell Death Dis. 2011 Oct 6;2:e212. doi: 10.1038/cddis.2011.93.
PMID 21975294
 
Regulation of CD95/Fas signaling at the DISC.
Lavrik IN, Krammer PH.
Cell Death Differ. 2012 Jan;19(1):36-41. doi: 10.1038/cdd.2011.155. Epub 2011 Nov 11. (REVIEW)
PMID 22075988
 
Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling.
Lemmers B, Salmena L, Bidere N, Su H, Matysiak-Zablocki E, Murakami K, Ohashi PS, Jurisicova A, Lenardo M, Hakem R, Hakem A.
J Biol Chem. 2007 Mar 9;282(10):7416-23. Epub 2007 Jan 9.
PMID 17213198
 
A novel single amino acid deletion caspase-8 mutant in cancer cells that lost proapoptotic activity.
Liu B, Peng D, Lu Y, Jin W, Fan Z.
J Biol Chem. 2002 Aug 16;277(33):30159-64. Epub 2002 Jun 7.
PMID 12055196
 
A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.
Mandruzzato S, Brasseur F, Andry G, Boon T, van der Bruggen P.
J Exp Med. 1997 Aug 29;186(5):785-93.
PMID 9271594
 
The Gene Expression Barcode: leveraging public data repositories to begin cataloging the human and murine transcriptomes.
McCall MN, Uppal K, Jaffee HA, Zilliox MJ, Irizarry RA.
Nucleic Acids Res. 2011 Jan;39(Database issue):D1011-5. doi: 10.1093/nar/gkq1259.
PMID 21177656
 
FLICE is activated by association with the CD95 death-inducing signaling complex (DISC).
Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH, Peter ME.
EMBO J. 1997 May 15;16(10):2794-804.
PMID 9184224
 
Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules.
Mielgo A, Torres VA, Clair K, Barbero S, Stupack DG.
Oncogene. 2009 Oct 8;28(40):3551-62. doi: 10.1038/onc.2009.210. Epub 2009 Aug 10.
PMID 19668227
 
FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex.
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM.
Cell. 1996 Jun 14;85(6):817-27.
PMID 8681377
 
Dynamics within the CD95 death-inducing signaling complex decide life and death of cells.
Neumann L, Pforr C, Beaudouin J, Pappa A, Fricker N, Krammer PH, Lavrik IN, Eils R.
Mol Syst Biol. 2010;6:352. doi: 10.1038/msb.2010.6. Epub 2010 Mar 9.
PMID 20212524
 
Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma.
Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T, Grotzer MA.
Clin Cancer Res. 2003 Dec 15;9(17):6401-9.
PMID 14695141
 
Pro-caspase-8 is predominantly localized in mitochondria and released into cytoplasm upon apoptotic stimulation.
Qin ZH, Wang Y, Kikly KK, Sapp E, Kegel KB, Aronin N, DiFiglia M.
J Biol Chem. 2001 Mar 16;276(11):8079-86. Epub 2000 Dec 1.
PMID 11102441
 
Differential modulation of apoptosis sensitivity in CD95 type I and type II cells.
Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME.
J Biol Chem. 1999 Aug 6;274(32):22532-8.
PMID 10428830
 
Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model.
Schleich K, Warnken U, Fricker N, Ozturk S, Richter P, Kammerer K, Schnolzer M, Krammer PH, Lavrik IN.
Mol Cell. 2012 Jul 27;47(2):306-19. doi: 10.1016/j.molcel.2012.05.006. Epub 2012 Jun 7.
PMID 22683265
 
Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas.
Soung YH, Lee JW, Kim SY, Sung YJ, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH.
Oncogene. 2005b Jan 6;24(1):141-7.
PMID 15531912
 
Potentiation of neuroblastoma metastasis by loss of caspase-8.
Stupack DG, Teitz T, Potter MD, Mikolon D, Houghton PJ, Kidd VJ, Lahti JM, Cheresh DA.
Nature. 2006 Jan 5;439(7072):95-9.
PMID 16397500
 
Requirement for caspase-8 in NF-kappaB activation by antigen receptor.
Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J, Salmena L, Hakem R, Straus S, Lenardo M.
Science. 2005 Mar 4;307(5714):1465-8.
PMID 15746428
 
Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma.
Takita J, Yang HW, Chen YY, Hanada R, Yamamoto K, Teitz T, Kidd V, Hayashi Y.
Oncogene. 2001 Jul 19;20(32):4424-32.
PMID 11466626
 
Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN.
Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ.
Nat Med. 2000 May;6(5):529-35.
PMID 10802708
 
The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.
Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P.
Mol Cell. 2011 Aug 5;43(3):432-48. doi: 10.1016/j.molcel.2011.06.006. Epub 2011 Jul 7.
PMID 21737329
 
A new caspase-8 isoform caspase-8s increased sensitivity to apoptosis in Jurkat cells.
Xu Z, Tang K, Wang M, Rao Q, Liu B, Wang J.
J Biomed Biotechnol. 2009;2009:930462. doi: 10.1155/2009/930462. Epub 2010 Jan 27.
PMID 20150972
 
Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism.
Yao Z, Duan S, Hou D, Heese K, Wu M.
EMBO J. 2007 Feb 21;26(4):1068-80. Epub 2007 Feb 8.
PMID 17290218
 
Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma.
Zuzak TJ, Steinhoff DF, Sutton LN, Phillips PC, Eggert A, Grotzer MA.
Eur J Cancer. 2002 Jan;38(1):83-91.
PMID 11750844
 

Citation

This paper should be referenced as such :
Öztürk, S ; Schleich, K ; Lavrik, IN
CASP8 (Caspase 8, Apoptosis-Related Cysteine Peptidase)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(6):372-377.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CASP8ID925ch2q33.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(2;5)(p23;q35) SQSTM1/ALK

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
  Breast: Ductal carcinoma

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ]
  Autoimmune lymphoproliferative syndrome Hereditary breast cancer

External links

Nomenclature
HGNC (Hugo)CASP8   1509
Cards
AtlasCASP8ID925ch2q33
Entrez_Gene (NCBI)CASP8  841  caspase 8
AliasesALPS2B; CAP4; Casp-8; FLICE; 
MACH; MCH5
GeneCards (Weizmann)CASP8
Ensembl hg19 (Hinxton)ENSG00000064012 [Gene_View]  chr2:202098166-202152434 [Contig_View]  CASP8 [Vega]
Ensembl hg38 (Hinxton)ENSG00000064012 [Gene_View]  chr2:202098166-202152434 [Contig_View]  CASP8 [Vega]
ICGC DataPortalENSG00000064012
TCGA cBioPortalCASP8
AceView (NCBI)CASP8
Genatlas (Paris)CASP8
WikiGenes841
SOURCE (Princeton)CASP8
Genomic and cartography
GoldenPath hg19 (UCSC)CASP8  -     chr2:202098166-202152434 +  2q33-q34   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CASP8  -     2q33-q34   [Description]    (hg38-Dec_2013)
EnsemblCASP8 - 2q33-q34 [CytoView hg19]  CASP8 - 2q33-q34 [CytoView hg38]
Mapping of homologs : NCBICASP8 [Mapview hg19]  CASP8 [Mapview hg38]
OMIM114480   114550   211980   601763   607271   
Gene and transcription
Genbank (Entrez)AA312258 AB451282 AB451414 AF009620 AF380342
RefSeq transcript (Entrez)NM_001080124 NM_001080125 NM_001228 NM_033355 NM_033356 NM_033357 NM_033358
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_007497 NT_005403 NW_004929305
Consensus coding sequences : CCDS (NCBI)CASP8
Cluster EST : UnigeneHs.599762 [ NCBI ]
CGAP (NCI)Hs.599762
Alternative Splicing GalleryENSG00000064012
Gene ExpressionCASP8 [ NCBI-GEO ]   CASP8 [ EBI - ARRAY_EXPRESS ]   CASP8 [ SEEK ]   CASP8 [ MEM ]
Gene Expression Viewer (FireBrowse)CASP8 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)841
GTEX Portal (Tissue expression)CASP8
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14790 (Uniprot)
NextProtQ14790  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14790
Splice isoforms : SwissVarQ14790 (Swissvar)
Catalytic activity : Enzyme3.4.22.61 [ Enzyme-Expasy ]   3.4.22.613.4.22.61 [ IntEnz-EBI ]   3.4.22.61 [ BRENDA ]   3.4.22.61 [ KEGG ]   
PhosPhoSitePlusQ14790
Domaine pattern : Prosite (Expaxy)CASPASE_CYS (PS01122)    CASPASE_HIS (PS01121)    CASPASE_P10 (PS50207)    CASPASE_P20 (PS50208)    DED (PS50168)   
Domains : Interpro (EBI)Caspase-like_dom    Caspase_cys_AS    Caspase_his_AS    DEATH-like_dom    DED_dom    Pept_C14_p10    Pept_C14_p20    Pept_C14A_HD   
Domain families : Pfam (Sanger)DED (PF01335)   
Domain families : Pfam (NCBI)pfam01335   
Domain families : Smart (EMBL)CASc (SM00115)  DED (SM00031)  
DMDM Disease mutations841
Blocks (Seattle)CASP8
PDB (SRS)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
PDB (PDBSum)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
PDB (IMB)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
PDB (RSDB)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
Structural Biology KnowledgeBase1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
SCOP (Structural Classification of Proteins)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
CATH (Classification of proteins structures)1F9E    1I4E    1QDU    1QTN    2C2Z    2FUN    2K7Z    2Y1L    3H11    3KJN    3KJQ    4JJ7    4PRZ    4PS1    4ZBW   
SuperfamilyQ14790
Human Protein AtlasENSG00000064012
Peptide AtlasQ14790
HPRD03459
IPIIPI00000149   IPI00220721   IPI00220722   IPI00305242   IPI00220723   IPI00220724   IPI00073318   IPI00220726   IPI00220725   IPI00816480   IPI00926515   IPI01011949   IPI00927151   IPI00927317   IPI00927011   
Protein Interaction databases
DIP (DOE-UCLA)Q14790
IntAct (EBI)Q14790
FunCoupENSG00000064012
BioGRIDCASP8
STRING (EMBL)CASP8
ZODIACCASP8
Ontologies - Pathways
QuickGOQ14790
Ontology : AmiGOcysteine-type endopeptidase activity  cysteine-type endopeptidase activity  death receptor binding  tumor necrosis factor receptor binding  protein binding  nucleoplasm  cytoplasm  mitochondrion  mitochondrial outer membrane  microtubule organizing center  cytosol  cytosol  cytoskeleton  proteolysis  apoptotic process  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  cellular component disassembly involved in execution phase of apoptosis  cell surface receptor signaling pathway  peptidase activity  cysteine-type peptidase activity  response to cold  regulation of tumor necrosis factor-mediated signaling pathway  regulation of necrotic cell death  natural killer cell activation  macrophage differentiation  death-inducing signaling complex  CD95 death-inducing signaling complex  ubiquitin protein ligase binding  response to cobalt ion  response to estradiol  protein complex binding  response to lipopolysaccharide  response to tumor necrosis factor  TRIF-dependent toll-like receptor signaling pathway  death effector domain binding  TRAIL-activated apoptotic signaling pathway  suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process  T cell activation  B cell activation  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of I-kappaB kinase/NF-kappaB signaling  negative regulation of I-kappaB kinase/NF-kappaB signaling  cell body  membrane raft  response to ethanol  positive regulation of macrophage differentiation  positive regulation of proteolysis  response to antibiotic  protein heterooligomerization  proteolysis involved in cellular protein catabolic process  syncytiotrophoblast cell differentiation involved in labyrinthine layer development  nucleotide-binding oligomerization domain containing signaling pathway  cellular response to mechanical stimulus  cellular response to organic cyclic compound  death-inducing signaling complex assembly  scaffold protein binding  cysteine-type endopeptidase activity involved in apoptotic process  apoptotic signaling pathway  apoptotic signaling pathway  extrinsic apoptotic signaling pathway  execution phase of apoptosis  cysteine-type endopeptidase activity involved in apoptotic signaling pathway  activation of cysteine-type endopeptidase activity  activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway  ripoptosome  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  
Ontology : EGO-EBIcysteine-type endopeptidase activity  cysteine-type endopeptidase activity  death receptor binding  tumor necrosis factor receptor binding  protein binding  nucleoplasm  cytoplasm  mitochondrion  mitochondrial outer membrane  microtubule organizing center  cytosol  cytosol  cytoskeleton  proteolysis  apoptotic process  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  cellular component disassembly involved in execution phase of apoptosis  cell surface receptor signaling pathway  peptidase activity  cysteine-type peptidase activity  response to cold  regulation of tumor necrosis factor-mediated signaling pathway  regulation of necrotic cell death  natural killer cell activation  macrophage differentiation  death-inducing signaling complex  CD95 death-inducing signaling complex  ubiquitin protein ligase binding  response to cobalt ion  response to estradiol  protein complex binding  response to lipopolysaccharide  response to tumor necrosis factor  TRIF-dependent toll-like receptor signaling pathway  death effector domain binding  TRAIL-activated apoptotic signaling pathway  suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process  T cell activation  B cell activation  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of I-kappaB kinase/NF-kappaB signaling  negative regulation of I-kappaB kinase/NF-kappaB signaling  cell body  membrane raft  response to ethanol  positive regulation of macrophage differentiation  positive regulation of proteolysis  response to antibiotic  protein heterooligomerization  proteolysis involved in cellular protein catabolic process  syncytiotrophoblast cell differentiation involved in labyrinthine layer development  nucleotide-binding oligomerization domain containing signaling pathway  cellular response to mechanical stimulus  cellular response to organic cyclic compound  death-inducing signaling complex assembly  scaffold protein binding  cysteine-type endopeptidase activity involved in apoptotic process  apoptotic signaling pathway  apoptotic signaling pathway  extrinsic apoptotic signaling pathway  execution phase of apoptosis  cysteine-type endopeptidase activity involved in apoptotic signaling pathway  activation of cysteine-type endopeptidase activity  activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway  ripoptosome  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  
Pathways : BIOCARTACeramide Signaling Pathway [Genes]    Role of Mitochondria in Apoptotic Signaling [Genes]    Induction of apoptosis through DR3 and DR4/5 Death Receptors [Genes]    D4-GDI Signaling Pathway [Genes]    FAS signaling pathway ( CD95 ) [Genes]    HIV-I Nef: negative effector of Fas and TNF [Genes]    SODD/TNFR1 Signaling Pathway [Genes]    Caspase Cascade in Apoptosis [Genes]    TNFR1 Signaling Pathway [Genes]   
Pathways : KEGGp53 signaling pathway    Apoptosis    Toll-like receptor signaling pathway    NOD-like receptor signaling pathway    RIG-I-like receptor signaling pathway    TNF signaling pathway    Non-alcoholic fatty liver disease (NAFLD)    Alzheimer's disease    Huntington's disease    Legionellosis    Chagas disease (American trypanosomiasis)    Toxoplasmosis    Tuberculosis    Hepatitis B    Herpes simplex infection    Pathways in cancer    Viral carcinogenesis    Viral myocarditis   
REACTOMEQ14790 [protein]
REACTOME PathwaysR-HSA-3371378 Regulation by c-FLIP [pathway]
REACTOME PathwaysR-HSA-75157 FasL/ CD95L signaling [pathway]
REACTOME PathwaysR-HSA-111465 Apoptotic cleavage of cellular proteins [pathway]
REACTOME PathwaysR-HSA-5660668 CLEC7A/inflammasome pathway [pathway]
REACTOME PathwaysR-HSA-140534 Ligand-dependent caspase activation [pathway]
REACTOME PathwaysR-HSA-69416 Dimerization of procaspase-8 [pathway]
REACTOME PathwaysR-HSA-75158 TRAIL signaling [pathway]
REACTOME PathwaysR-HSA-75108 Activation, myristolyation of BID and translocation to mitochondria [pathway]
REACTOME PathwaysR-HSA-75153 Apoptotic execution phase [pathway]
REACTOME PathwaysR-HSA-264870 Caspase-mediated cleavage of cytoskeletal proteins [pathway]
REACTOME PathwaysR-HSA-5213460 RIPK1-mediated regulated necrosis [pathway]
REACTOME PathwaysR-HSA-5218900 CASP8 activity is inhibited [pathway]
REACTOME PathwaysR-HSA-5357786 TNFR1-induced proapoptotic signaling [pathway]
REACTOME PathwaysR-HSA-168638 NOD1/2 Signaling Pathway [pathway]
REACTOME PathwaysR-HSA-933543 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 [pathway]
REACTOME PathwaysR-HSA-2562578 TRIF-mediated programmed cell death [pathway]
NDEx NetworkCASP8
Atlas of Cancer Signalling NetworkCASP8
Wikipedia pathwaysCASP8
Orthology - Evolution
OrthoDB841
GeneTree (enSembl)ENSG00000064012
Phylogenetic Trees/Animal Genes : TreeFamCASP8
Homologs : HomoloGeneCASP8
Homology/Alignments : Family Browser (UCSC)CASP8
Gene fusions - Rearrangements
Fusion : MitelmanACVR2A/CASP8 [2q22.3/2q33.1]  [t(2;2)(q22;q33)]  
Fusion : MitelmanCASP8/ALS2CR12 [2q33.1/2q33.1]  [t(2;2)(q33;q33)]  
Fusion : MitelmanCASP8/UBR3 [2q33.1/2q31.1]  [t(2;2)(q31;q33)]  
Fusion: TCGAACVR2A 2q22.3 CASP8 2q33.1 LUSC
Fusion: TCGACASP8 2q33.1 ALS2CR12 2q33.1 BRCA
Fusion: TCGACASP8 2q33.1 UBR3 2q31.1 LUAD
Polymorphisms : SNP, variants
NCBI Variation ViewerCASP8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CASP8
dbVarCASP8
ClinVarCASP8
1000_GenomesCASP8 
Exome Variant ServerCASP8
ExAC (Exome Aggregation Consortium)CASP8 (select the gene name)
Genetic variants : HAPMAP841
Genomic Variants (DGV)CASP8 [DGVbeta]
Mutations
ICGC Data PortalCASP8 
TCGA Data PortalCASP8 
Broad Tumor PortalCASP8
OASIS PortalCASP8 [ Somatic mutations - Copy number]
Cancer Gene: CensusCASP8 
Somatic Mutations in Cancer : COSMICCASP8 
intOGen PortalCASP8
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
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch CASP8
DgiDB (Drug Gene Interaction Database)CASP8
DoCM (Curated mutations)CASP8 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CASP8 (select a term)
intoGenCASP8
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)2:202098166-202152434  ENSG00000064012
CONAN: Copy Number AnalysisCASP8 
Mutations and Diseases : HGMDCASP8
OMIM114480    114550    211980    601763    607271   
MedgenCASP8
Genetic Testing Registry CASP8
NextProtQ14790 [Medical]
TSGene841
GENETestsCASP8
Huge Navigator CASP8 [HugePedia]
snp3D : Map Gene to Disease841
BioCentury BCIQCASP8
ClinGenCASP8
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD841
Chemical/Pharm GKB GenePA26092
Clinical trialCASP8
Miscellaneous
canSAR (ICR)CASP8 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCASP8
EVEXCASP8
GoPubMedCASP8
iHOPCASP8
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 : Wed Sep 28 15:50:52 CEST 2016

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

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.