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Gene Review

CASP8  -  caspase 8, apoptosis-related cysteine...

Homo sapiens

Synonyms: ALPS2B, Apoptotic cysteine protease, Apoptotic protease Mch-5, CAP4, CASP-8, ...
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Disease relevance of CASP8


Psychiatry related information on CASP8

  • These radiologic findings are an optical illusion (Mach band, background contrast effect) [9].
  • This hypothesis was addressed by assessing Mach IV psychometric scale performance in a group of 51 patients with schizophrenia and in 93 controls [10].
  • Visual illusions in computed tomography: phenomena related to Mach effect [11].
  • Machiavellianism: dimensionality of the Mach IV and its relation to self-monitoring in a Spanish sample [12].
  • To estimate this association in a sample of Turkish people, 361 physicians were selected among the total number of 5,959 working in Ankara City Center. A self-administered questionnaire including the Mach IV scale and Job Satisfaction scale developed by Kasapoğlu was applied to the subjects [13].

High impact information on CASP8


Chemical compound and disease context of CASP8


Biological context of CASP8


Anatomical context of CASP8


Associations of CASP8 with chemical compounds


Physical interactions of CASP8

  • In addition, MRIT simultaneously and independently interacts with BclXL and FLICE in mammalian cells [34].
  • FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk [35].
  • In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE [36].
  • Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis [37].

Regulatory relationships of CASP8


Other interactions of CASP8

  • Since the overall architecture and function of this molecule is similar to that of FLICE, it has been designated FLICE2 [45].
  • In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum [4].
  • Less frequent methylation was observed for CASP8, MGMT and TP73 (5-20%) [46].
  • However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R/Q)G [34].
  • Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases [31].

Analytical, diagnostic and therapeutic context of CASP8

  • Western blots showed that FLICE/caspase-8 was upregulated and activated by 24 hours of incubation with IFNgamma [47].
  • Western blots of ICE/caspase-1, which might be required for amplification of the initial FLICE activation signal, showed that pro-ICE expression significantly increased after treatment with IFNgamma for 24 hours and cleavage of pro-ICE also increased [47].
  • Flow cytometry of fresh erythroblasts revealed a considerable expression of the caspases CPP32 and FLICE in both their constitutive proenzymatic forms and in cleaved subunits [48].
  • Ceramide, in contrast to Fas ligation, did not induce activation of caspase-8/FLICE and neither SPP nor TPA were able to prevent this activation [49].
  • Silicon phthalocyanine 4 photodynamic therapy also caused a significant activation of FLICE, as evident from the appearance of cleaved products of pro-caspase 8 [50].


  1. Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. Teitz, T., Wei, T., Liu, D., Valentine, V., Valentine, M., Grenet, J., Lahti, J.M., Kidd, V.J. Oncogene (2002) [Pubmed]
  2. Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification. Shivapurkar, N., Reddy, J., Matta, H., Sathyanarayana, U.G., Huang, C.X., Toyooka, S., Minna, J.D., Chaudhary, P.M., Gazdar, A.F. Oncogene (2002) [Pubmed]
  3. Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant. Frank, B., Hemminki, K., Wappenschmidt, B., Meindl, A., Klaes, R., Schmutzler, R.K., Bugert, P., Untch, M., Bartram, C.R., Burwinkel, B. Carcinogenesis (2006) [Pubmed]
  4. Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profiling. Lindsey, J.C., Lusher, M.E., Anderton, J.A., Bailey, S., Gilbertson, R.J., Pearson, A.D., Ellison, D.W., Clifford, S.C. Carcinogenesis (2004) [Pubmed]
  5. Methylation of RASSF1A and TRAIL pathway-related genes is frequent in childhood intracranial ependymomas and benign choroid plexus papilloma. Michalowski, M.B., de Fraipont, F., Michelland, S., Entz-Werle, N., Grill, J., Pasquier, B., Favrot, M.C., Plantaz, D. Cancer Genet. Cytogenet. (2006) [Pubmed]
  6. CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Martinez, R., Setien, F., Voelter, C., Casado, S., Quesada, M.P., Schackert, G., Esteller, M. Carcinogenesis (2007) [Pubmed]
  7. Interferon-gamma sensitizes resistant Ewing's sarcoma cells to tumor necrosis factor apoptosis-inducing ligand-induced apoptosis by up-regulation of caspase-8 without altering chemosensitivity. Lissat, A., Vraetz, T., Tsokos, M., Klein, R., Braun, M., Koutelia, N., Fisch, P., Romero, M.E., Long, L., Noellke, P., Mackall, C.L., Niemeyer, C.M., Kontny, U. Am. J. Pathol. (2007) [Pubmed]
  8. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter associated with risk and progression of bladder cancer. Wang, M., Zhang, Z., Tian, Y., Shao, J., Zhang, Z. Clin. Cancer Res. (2009) [Pubmed]
  9. Mach bands in mammography. Gordenne, W.H., Malchair, F.L. Radiology. (1988) [Pubmed]
  10. Social deficits associated with schizophrenia defined in terms of interpersonal Machiavellianism. Sullivan, R.J., Allen, J.S. Acta psychiatrica Scandinavica. (1999) [Pubmed]
  11. Visual illusions in computed tomography: phenomena related to Mach effect. Daffner, R.H. AJR. American journal of roentgenology. (1980) [Pubmed]
  12. Machiavellianism: dimensionality of the Mach IV and its relation to self-monitoring in a Spanish sample. Corral, S., Calvete, E. The Spanish journal of psychology. (2000) [Pubmed]
  13. Relation between Machiavellianism and job satisfaction in a sample of Turkish physicians. Bakir, B., Ozer, M., Uçar, M., Güleç, M., Demir, C., Hasde, M. Psychological reports. (2003) [Pubmed]
  14. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Boldin, M.P., Goncharov, T.M., Goltsev, Y.V., Wallach, D. Cell (1996) [Pubmed]
  15. Expression and methylation of CASP8 in neuroblastoma: identification of a promoter region. Banelli, B., Casciano, I., Croce, M., Di Vinci, A., Gelvi, I., Pagnan, G., Brignole, C., Allemanni, G., Ferrini, S., Ponzoni, M., Romani, M. Nat. Med. (2002) [Pubmed]
  16. Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D. Olsson, A., Diaz, T., Aguilar-Santelises, M., Osterborg, A., Celsing, F., Jondal, M., Osorio, L.M. Leukemia (2001) [Pubmed]
  17. Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines. Yamada, Y., Sugahara, K., Tsuruda, K., Nohda, K., Mori, N., Hata, T., Maeda, T., Hayashibara, T., Joh, T., Honda, M., Tawara, M., Tomonaga, M., Miyazaki, Y., Kamihira, S. Eur. J. Haematol. (2000) [Pubmed]
  18. Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Watanabe, K., Okamoto, K., Yonehara, S. Cell Death Differ. (2005) [Pubmed]
  19. Induction of Apoptosis in Estrogen Receptor-Negative Breast Cancer Cells by Natural and Synthetic Cyclopentenones: Role of the I{kappa}B Kinase/Nuclear Factor-{kappa}B Pathway. Ciucci, A., Gianferretti, P., Piva, R., Guyot, T., Snape, T.J., Roberts, S.M., Santoro, M.G. Mol. Pharmacol. (2006) [Pubmed]
  20. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study. Lind, T., Veldhuyzen van Zanten, S., Unge, P., Spiller, R., Bayerdörffer, E., O'Morain, C., Bardhan, K.D., Bradette, M., Chiba, N., Wrangstadh, M., Cederberg, C., Idström, J.P. Helicobacter (1996) [Pubmed]
  21. Multigene methylation analysis of Wilms' tumour and adult renal cell carcinoma. Morris, M.R., Hesson, L.B., Wagner, K.J., Morgan, N.V., Astuti, D., Lees, R.D., Cooper, W.N., Lee, J., Gentle, D., Macdonald, F., Kishida, T., Grundy, R., Yao, M., Latif, F., Maher, E.R. Oncogene (2003) [Pubmed]
  22. Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. Yang, Q., Zage, P., Kagan, D., Tian, Y., Seshadri, R., Salwen, H.R., Liu, S., Chlenski, A., Cohn, S.L. Clin. Cancer Res. (2004) [Pubmed]
  23. Structure and chromosome localization of the human CASP8 gene. Grenet, J., Teitz, T., Wei, T., Valentine, V., Kidd, V.J. Gene (1999) [Pubmed]
  24. p21(WAF1/CIP1) inhibits initiator caspase cleavage by TRAIL death receptor DR4. Xu, S.Q., El-Deiry, W.S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  25. Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin in medulloblastoma. Ebinger, M., Senf, L., Wachowski, O., Scheurlen, W. Pathol. Oncol. Res. (2004) [Pubmed]
  26. Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex. Peter, M.E., Kischkel, F.C., Scheuerpflug, C.G., Medema, J.P., Debatin, K.M., Krammer, P.H. Eur. J. Immunol. (1997) [Pubmed]
  27. Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis. Leverkus, M., Walczak, H., McLellan, A., Fries, H.W., Terbeck, G., Bröcker, E.B., Kämpgen, E. Blood (2000) [Pubmed]
  28. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Zhang, X.D., Franco, A., Myers, K., Gray, C., Nguyen, T., Hersey, P. Cancer Res. (1999) [Pubmed]
  29. Caspase-8 gene expression in neuroblastoma. Casciano, I., Banelli, B., Croce, M., De Ambrosis, A., di Vinci, A., Gelvi, I., Pagnan, G., Brignole, C., Allemanni, G., Ferrini, S., Ponzoni, M., Romani, M. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  30. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). Medema, J.P., Scaffidi, C., Kischkel, F.C., Shevchenko, A., Mann, M., Krammer, P.H., Peter, M.E. EMBO J. (1997) [Pubmed]
  31. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., Litwack, G., Alnemri, E.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  32. Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood. Mühlisch, J., Schwering, A., Grotzer, M., Vince, G.H., Roggendorf, W., Hagemann, C., Sörensen, N., Rickert, C.H., Osada, N., Jürgens, H., Frühwald, M.C. Oncogene (2006) [Pubmed]
  33. Identification of a critical tyrosine residue in caspase 8 that promotes cell migration. Barbero, S., Barilà, D., Mielgo, A., Stagni, V., Clair, K., Stupack, D. J. Biol. Chem. (2008) [Pubmed]
  34. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Han, D.K., Chaudhary, P.M., Wright, M.E., Friedman, C., Trask, B.J., Riedel, R.T., Baskin, D.G., Schwartz, S.M., Hood, L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  35. 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, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E., Dixit, V.M. Cell (1996) [Pubmed]
  36. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Chinnaiyan, A.M., O'Rourke, K., Lane, B.R., Dixit, V.M. Science (1997) [Pubmed]
  37. Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. Jia, S.H., Parodo, J., Kapus, A., Rotstein, O.D., Marshall, J.C. J. Biol. Chem. (2008) [Pubmed]
  38. E2F1 induces apoptosis and sensitizes human lung adenocarcinoma cells to death-receptor-mediated apoptosis through specific downregulation of c-FLIP(short). Salon, C., Eymin, B., Micheau, O., Chaperot, L., Plumas, J., Brambilla, C., Brambilla, E., Gazzeri, S. Cell Death Differ. (2006) [Pubmed]
  39. Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis. Chen, P., Tian, J., Kovesdi, I., Bruder, J.T. J. Biol. Chem. (1998) [Pubmed]
  40. TCR engagement regulates differential responsiveness of human memory T cells to Fas (CD95)-mediated apoptosis. Di Somma, M.M., Somma, F., Gilardini Montani, M.S., Mangiacasale, R., Cundari, E., Piccolella, E. J. Immunol. (1999) [Pubmed]
  41. Fibroblast-like synoviocytes from rheumatoid arthritis patients express less FLICE-inhibitory protein than fibroblast-like synoviocytes from trauma patients: comment on the article by Schedel et al. Tolboom, T.C., Medema, J.P., van Gaalen, F.A., Pieterman, E., Huizinga, T.W., Toes, R.E. Arthritis Rheum. (2003) [Pubmed]
  42. p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death. El Mchichi, B., Hadji, A., Vazquez, A., Leca, G. Cell Death Differ. (2007) [Pubmed]
  43. 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) [Pubmed]
  44. Caspase 8 promotes peripheral localization and activation of Rab5. Torres, V.A., Mielgo, A., Barilà, D., Anderson, D.H., Stupack, D. J. Biol. Chem. (2008) [Pubmed]
  45. Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. Vincenz, C., Dixit, V.M. J. Biol. Chem. (1997) [Pubmed]
  46. Epigenetic inactivation of the RASSF1A tumour suppressor gene in ependymoma. Hamilton, D.W., Lusher, M.E., Lindsey, J.C., Ellison, D.W., Clifford, S.C. Cancer Lett. (2005) [Pubmed]
  47. Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Dai, C., Krantz, S.B. Blood (1999) [Pubmed]
  48. Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. Silvestris, F., Tucci, M., Cafforio, P., Dammacco, F. Blood (2001) [Pubmed]
  49. Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. Cuvillier, O., Rosenthal, D.S., Smulson, M.E., Spiegel, S. J. Biol. Chem. (1998) [Pubmed]
  50. Involvement of Fas (APO-1/CD-95) during photodynamic-therapy-mediated apoptosis in human epidermoid carcinoma A431 cells. Ahmad, N., Gupta, S., Feyes, D.K., Mukhtar, H. J. Invest. Dermatol. (2000) [Pubmed]
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