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Gene Review

Casp8  -  caspase 8

Mus musculus

Synonyms: CASP-8, Caspase-8, FLICE, MACH, Mch5
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Disease relevance of Casp8


High impact information on Casp8

  • BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization [6].
  • Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis [7].
  • Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy [8].
  • Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation [9].
  • Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency [10].

Chemical compound and disease context of Casp8


Biological context of Casp8


Anatomical context of Casp8

  • Rather, Casp8-deficient B cells failed to proliferate in response to dsRNA and LPS, ligands for TLR3 and TLR4, respectively, but responded normally to the TLR9 agonist CpG DNA [18].
  • The Caspase 8 null embryos exhibited impaired heart muscle development and congested accumulation of erythrocytes [19].
  • Cellular FLICE-inhibitory protein is required for T cell survival and cycling [20].
  • During both apoptosis signalling and mitogenic activation, FADD and caspase-8 aggregated in multiprotein complexes and formed caps at the plasma membrane but they did not colocalise with lipid rafts [21].
  • Mitochondria significantly amplified the caspase-8 initiated DEVD-specific cleavage activity [22].

Associations of Casp8 with chemical compounds


Physical interactions of Casp8


Enzymatic interactions of Casp8


Regulatory relationships of Casp8


Other interactions of Casp8

  • We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome [24].
  • We generated novel monoclonal antibodies specific for mouse FADD and caspase-8 to investigate whether cellular responses, apoptosis or proliferation, might be explained by differences in post-translational modification and subcellular localisation of these proteins [21].
  • Procaspase-2 was maturated by caspase-8 and -3, and to a lesser extent by caspase-7, while the active caspase-2 did not process any of the procaspases examined, except its own precursor [38].
  • Fas recruits caspase 8, which initiates the death program through the subsequent activation of caspase 3 [39].
  • We have, for the first time, identified a predominant role for the caspase-8/Bid pathway in signaling associated with hyperoxic lung injury and cell death in vivo and in vitro [40].

Analytical, diagnostic and therapeutic context of Casp8


  1. Silencing of caspase-8 in murine hepatocellular carcinomas is mediated via methylation of an essential promoter element. Liedtke, C., Zschemisch, N.H., Cohrs, A., Roskams, T., Borlak, J., Manns, M.P., Trautwein, C. Gastroenterology (2005) [Pubmed]
  2. Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2. Benchoua, A., Couriaud, C., Guégan, C., Tartier, L., Couvert, P., Friocourt, G., Chelly, J., Ménissier-de Murcia, J., Onténiente, B. J. Biol. Chem. (2002) [Pubmed]
  3. Caspase-8 and Apaf-1-independent caspase-9 activation in Sendai virus-infected cells. Bitzer, M., Armeanu, S., Prinz, F., Ungerechts, G., Wybranietz, W., Spiegel, M., Bernlöhr, C., Cecconi, F., Gregor, M., Neubert, W.J., Schulze-Osthoff, K., Lauer, U.M. J. Biol. Chem. (2002) [Pubmed]
  4. Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. Kassis, R., Larrous, F., Estaquier, J., Bourhy, H. J. Virol. (2004) [Pubmed]
  5. Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice. Huber, S., Dohrman, A., Sartini, D., Budd, R.C. Immunology (2006) [Pubmed]
  6. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. McDonnell, J.M., Fushman, D., Milliman, C.L., Korsmeyer, S.J., Cowburn, D. Cell (1999) [Pubmed]
  7. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Li, H., Zhu, H., Xu, C.J., Yuan, J. Cell (1998) [Pubmed]
  8. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Pajvani, U.B., Trujillo, M.E., Combs, T.P., Iyengar, P., Jelicks, L., Roth, K.A., Kitsis, R.N., Scherer, P.E. Nat. Med. (2005) [Pubmed]
  9. Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. LeBlanc, H., Lawrence, D., Varfolomeev, E., Totpal, K., Morlan, J., Schow, P., Fong, S., Schwall, R., Sinicropi, D., Ashkenazi, A. Nat. Med. (2002) [Pubmed]
  10. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Chun, H.J., Zheng, L., Ahmad, M., Wang, J., Speirs, C.K., Siegel, R.M., Dale, J.K., Puck, J., Davis, J., Hall, C.G., Skoda-Smith, S., Atkinson, T.P., Straus, S.E., Lenardo, M.J. Nature (2002) [Pubmed]
  11. Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. Viswanath, V., Wu, Y., Boonplueang, R., Chen, S., Stevenson, F.F., Yantiri, F., Yang, L., Beal, M.F., Andersen, J.K. J. Neurosci. (2001) [Pubmed]
  12. Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression. Kurdow, R., Schniewind, B., Zoefelt, S., Boenicke, L., Boehle, A.S., Dohrmann, P., Kalthoff, H. Langenbeck's archives of surgery / Deutsche Gesellschaft für Chirurgie. (2005) [Pubmed]
  13. Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas. Herr, I., Ucur, E., Herzer, K., Okouoyo, S., Ridder, R., Krammer, P.H., von Knebel Doeberitz, M., Debatin, K.M. Cancer Res. (2003) [Pubmed]
  14. Crm-A, bcl-2 and NDGA inhibit CD95L-induced apoptosis of malignant glioma cells at the level of caspase 8 processing. Wagenknecht, B., Schulz, J.B., Gulbins, E., Weller, M. Cell Death Differ. (1998) [Pubmed]
  15. Liver protection from apoptosis requires both blockage of initiator caspase activities and inhibition of ASK1/JNK pathway via glutathione S-transferase regulation. Gilot, D., Loyer, P., Corlu, A., Glaise, D., Lagadic-Gossmann, D., Atfi, A., Morel, F., Ichijo, H., Guguen-Guillouzo, C. J. Biol. Chem. (2002) [Pubmed]
  16. Comparative genomic analysis of genes encoding translation elongation factor 1B(alpha) in human and mouse shows EEF1B1 to be a recent retrotransposition event. Chambers, D.M., Rouleau, G.A., Abbott, C.M. Genomics (2001) [Pubmed]
  17. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Yeh, W.C., Itie, A., Elia, A.J., Ng, M., Shu, H.B., Wakeham, A., Mirtsos, C., Suzuki, N., Bonnard, M., Goeddel, D.V., Mak, T.W. Immunity (2000) [Pubmed]
  18. Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. Beisner, D.R., Ch'en, I.L., Kolla, R.V., Hoffmann, A., Hedrick, S.M. J. Immunol. (2005) [Pubmed]
  19. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Varfolomeev, E.E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J.S., Mett, I.L., Rebrikov, D., Brodianski, V.M., Kemper, O.C., Kollet, O., Lapidot, T., Soffer, D., Sobe, T., Avraham, K.B., Goncharov, T., Holtmann, H., Lonai, P., Wallach, D. Immunity (1998) [Pubmed]
  20. Cellular FLICE-inhibitory protein is required for T cell survival and cycling. Chau, H., Wong, V., Chen, N.J., Huang, H.L., Lin, W.J., Mirtsos, C., Elford, A.R., Bonnard, M., Wakeham, A., You-Ten, A.I., Lemmers, B., Salmena, L., Pellegrini, M., Hakem, R., Mak, T.W., Ohashi, P., Yeh, W.C. J. Exp. Med. (2005) [Pubmed]
  21. Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes. O'Reilly, L.A., Divisekera, U., Newton, K., Scalzo, K., Kataoka, T., Puthalakath, H., Ito, M., Huang, D.C., Strasser, A. Cell Death Differ. (2004) [Pubmed]
  22. Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. Bossy-Wetzel, E., Green, D.R. J. Biol. Chem. (1999) [Pubmed]
  23. Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Marchetti, M.C., Di Marco, B., Cifone, G., Migliorati, G., Riccardi, C. Blood (2003) [Pubmed]
  24. Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells. McDonnell, M.A., Wang, D., Khan, S.M., Vander Heiden, M.G., Kelekar, A. Cell Death Differ. (2003) [Pubmed]
  25. Caspase-8 serves both apoptotic and nonapoptotic roles. Kang, T.B., Ben-Moshe, T., Varfolomeev, E.E., Pewzner-Jung, Y., Yogev, N., Jurewicz, A., Waisman, A., Brenner, O., Haffner, R., Gustafsson, E., Ramakrishnan, P., Lapidot, T., Wallach, D. J. Immunol. (2004) [Pubmed]
  26. Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. Wang, Y., Singh, R., Lefkowitch, J.H., Rigoli, R.M., Czaja, M.J. J. Biol. Chem. (2006) [Pubmed]
  27. Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis. Carson, C., Saleh, M., Fung, F.W., Nicholson, D.W., Roskams, A.J. J. Neurosci. (2005) [Pubmed]
  28. Oocyte attrition. Reynaud, K., Driancourt, M.A. Mol. Cell. Endocrinol. (2000) [Pubmed]
  29. NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy. Ross, M.J., Martinka, S., D'Agati, V.D., Bruggeman, L.A. J. Am. Soc. Nephrol. (2005) [Pubmed]
  30. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Ricci, M.S., Jin, Z., Dews, M., Yu, D., Thomas-Tikhonenko, A., Dicker, D.T., El-Deiry, W.S. Mol. Cell. Biol. (2004) [Pubmed]
  31. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. Ferrer, I., Planas, A.M. J. Neuropathol. Exp. Neurol. (2003) [Pubmed]
  32. Expression of dominant-negative Fas-associated death domain blocks human keratinocyte apoptosis and vesication induced by sulfur mustard. Rosenthal, D.S., Velena, A., Chou, F.P., Schlegel, R., Ray, R., Benton, B., Anderson, D., Smith, W.J., Simbulan-Rosenthal, C.M. J. Biol. Chem. (2003) [Pubmed]
  33. Ion channel activity of the BH3 only Bcl-2 family member, BID. Schendel, S.L., Azimov, R., Pawlowski, K., Godzik, A., Kagan, B.L., Reed, J.C. J. Biol. Chem. (1999) [Pubmed]
  34. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. Krueger, A., Schmitz, I., Baumann, S., Krammer, P.H., Kirchhoff, S. J. Biol. Chem. (2001) [Pubmed]
  35. TNF-alpha in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes. Alikhani, M., Alikhani, Z., Raptis, M., Graves, D.T. J. Cell. Physiol. (2004) [Pubmed]
  36. TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Schlapbach, R., Spanaus, K.S., Malipiero, U., Lens, S., Tasinato, A., Tschopp, J., Fontana, A. Eur. J. Immunol. (2000) [Pubmed]
  37. Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor- and Fas-mediated hepatocyte apoptosis in mice. Imao, M., Nagaki, M., Imose, M., Moriwaki, H. Liver Int. (2006) [Pubmed]
  38. The proteolytic procaspase activation network: an in vitro analysis. Van de Craen, M., Declercq, W., Van den brande, I., Fiers, W., Vandenabeele, P. Cell Death Differ. (1999) [Pubmed]
  39. Cytotoxic T lymphocyte-assisted suicide. Caspase 3 activation is primarily the result of the direct action of granzyme B. Atkinson, E.A., Barry, M., Darmon, A.J., Shostak, I., Turner, P.C., Moyer, R.W., Bleackley, R.C. J. Biol. Chem. (1998) [Pubmed]
  40. Necrotic cell death in response to oxidant stress involves the activation of the apoptogenic caspase-8/bid pathway. Wang, X., Ryter, S.W., Dai, C., Tang, Z.L., Watkins, S.C., Yin, X.M., Song, R., Choi, A.M. J. Biol. Chem. (2003) [Pubmed]
  41. Role of FLASH in caspase-8-mediated activation of NF-kappaB: dominant-negative function of FLASH mutant in NF-kappaB signaling pathway. Jun, J.I., Chung, C.W., Lee, H.J., Pyo, J.O., Lee, K.N., Kim, N.S., Kim, Y.S., Yoo, H.S., Lee, T.H., Kim, E., Jung, Y.K. Oncogene (2005) [Pubmed]
  42. Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice. Contreras, J.L., Vilatoba, M., Eckstein, C., Bilbao, G., Anthony Thompson, J., Eckhoff, D.E. Surgery (2004) [Pubmed]
  43. Molecular cloning and characterization of mouse caspase-8. Sakamaki, K., Tsukumo, S., Yonehara, S. Eur. J. Biochem. (1998) [Pubmed]
  44. Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. Shah, S., Sylvester, P.W. Exp. Biol. Med. (Maywood) (2004) [Pubmed]
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