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Gene Review

CASP8AP2  -  caspase 8 associated protein 2

Homo sapiens

Synonyms: CASP8-associated protein 2, CED-4, FLASH, FLICE-associated huge protein, FLJ11208, ...
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Disease relevance of CASP8AP2


Psychiatry related information on CASP8AP2

  • RESULTS: Flash electroretinogram revealed a significant decrease in the amplitude of the B1 wave (<60 microV) and the B/A ratio (<2) in the CJD group compared with those in the control group [6].
  • 1. Flash visual evoked responses of 31 patients meeting DSM-III-R criteria for primary degenerative dementia of the Alzheimer type were compared with 31 healthy controls [7].

High impact information on CASP8AP2

  • Intriguingly, CED-4 comprises a AAA+ type ATPase domain yet does not seem to need ATP hydrolysis for activity [8].
  • Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development [9].
  • In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2-like protein CED-9 [10].
  • In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE [11].
  • Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases [11].

Biological context of CASP8AP2

  • The caspase 8-associated protein 2 (CASP8AP2) gene was studied further because of its reported role in apoptosis and glucocorticoid signaling [1].
  • In a separate cohort of 99 patients not included in the comparison of gene expression profiles and MRD, low levels of CASP8AP2 expression predicted a lower event-free survival (P = .02) and a higher rate of leukemia relapse (P = .01) and were an independent predictor of outcome [1].
  • Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death [11].
  • Two loss-of-function point mutations in different regions of CED-4 also lead to a significant loss of interaction suggesting further that the relevant interaction domains are not short linear sequences, but rather, are formed by more complex structural determinants in each molecule [12].
  • Recently recognised structural and amino acid sequence similarities between plant disease resistance (R) proteins and animal proteins such as Apaf-1 and CED-4 are providing conceptual models for resistance protein function [13].

Anatomical context of CASP8AP2

  • Expression of CED-9, but not a mutant lacking the carboxy-terminal hydrophobic domain, targeted CED-4 from the cytosol to intracellular membranes in mammalian cells [14].
  • Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria [15].
  • 1. Flash photolysis of caged compounds of phenylephrine, inositol 1, 4, 5 trisphosphate (InsP3), GTP gamma S, ATP, and CTP has been successfully used to study excitation-contraction coupling, contractile regulation, and contraction in smooth muscle [16].
  • In cells undergoing apoptosis, the Bcl-2 homology domain 3 (BH3)-only protein EGL-1 binds to CED-9 at the mitochondrial membrane to cause the release of CED-4, which oligomerises and facilitates the activation of the caspase CED-3 [17].
  • Reconstitution of isotonic conditions with specific osmoles or inhibition with mechanosensitive ion channel blockers dampened hypotonicity-induced ATP release. "Flash-frozen" cyst fluids from ADPKD cysts, harvested from multiple donor kidneys, were screened by luminometry [18].

Associations of CASP8AP2 with chemical compounds

  • Significantly, however, Bcl-xL lacking BH4 lost the ability both to bind CED-4 and antagonize its pro-apoptotic activity [19].
  • Lastly, we show that a BH3 peptide that can inhibit Bcl-2 family interactions also inhibits the interaction between Bcl-x(L) and CED-4 [12].
  • 5. Flash photolysis at pH 5.5 caused rapid production of L-glutamate within the synaptic cleft and a fast postsynaptic depolarization which generated postsynaptic action potentials.(ABSTRACT TRUNCATED AT 250 WORDS)[20]
  • 7. Flash photolysis of nifedipine in the interval between conditioning and test pulse showed that the predepolarization causes a rate-enhancing effect even though the slow channels were blocked by nifedipine during the conditioning pulse [21].
  • DESIGN: Conventional biological indicators tested included the conventional Attest 1261, Proof Flash and Assert, while the rapid readout indicator tested was Attest 1291 [22].

Regulatory relationships of CASP8AP2

  • Caspase-8-binding protein FLICE-associated huge protein (FLASH) has been proposed to regulate death receptor CD95-induced apoptosis through facilitating caspase-8 activation at the death-inducing signaling complex [23].
  • Mutational analysis revealed that only a small portion of the CED-4 homologous region (residues 456-559) could be deleted without destroying the ability of Apaf-1-(1-559) to activate pro-casp9 [24].
  • Expression of Apaf-1 enhanced the killing activity of caspase-9 that required the CED-4-like domain of Apaf-1 [25].
  • Apaf-1 is a mammalian homolog of CED-4 that regulates cell death by participating in a ternary complex with cytochrome c, and procaspase-9 [26].

Other interactions of CASP8AP2

  • E1B 19,000-molecular-weight protein interacts with and inhibits CED-4-dependent, FLICE-mediated apoptosis [27].
  • However, it has remained unclear whether a mammalian CED-9 homologue, Bcl-XL, inhibits the function of the mammalian CED-4 homologue, Apaf-1, by direct binding [28].
  • Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53 [29].
  • PATIENTS AND METHODS: Flash electroretinogram (ERG) was studied in 15 unaffected patients (30 eyes) with constitutional BRCA1 gene mutation [30].
  • Programmed cell death in Caenorhabditis elegans is initiated by the binding of EGL-1 to CED-9, which disrupts the CED-4/CED-9 complex and allows CED-4 to activate the cell-killing caspase CED-3 [31].

Analytical, diagnostic and therapeutic context of CASP8AP2

  • We conclude that measurement of CASP8AP2 expression at diagnosis offers a means to identify patients whose leukemic cells are highly susceptible to chemotherapy [1].
  • Binding analysis indicated that E1B 19K interacts with CED-4 in a Saccharomyces cerevisiae two-hybrid assay, in vitro, and in mammalian cell lysates [27].
  • Significantly, the C-terminal region containing WD-40 repeats interacted with its N-terminal CED-4 homologous region, as determined by immunoprecipitation experiments [24].
  • In addition to T2 weighted sequences, T1 weighted two dimensional and three dimensional Flash acquisitions as well as volume rendered virtual endoscopy were performed [32].
  • CONCLUSIONS: Flash-freezing in LN without cryopreservative most closely reproduced the results obtained using fresh human semen samples, and thereby represents the most appropriate cryopreservation method for human semen in epidemiological studies utilizing the neutral comet assay [33].


  1. Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2. Flotho, C., Coustan-Smith, E., Pei, D., Iwamoto, S., Song, G., Cheng, C., Pui, C.H., Downing, J.R., Campana, D. Blood (2006) [Pubmed]
  2. Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina. Cohen, M., Lee, K.K., Wilson, K.L., Gruenbaum, Y. Trends Biochem. Sci. (2001) [Pubmed]
  3. The Tomato NBARC-LRR Protein Prf Interacts with Pto Kinase in Vivo to Regulate Specific Plant Immunity. Mucyn, T.S., Clemente, A., Andriotis, V.M., Balmuth, A.L., Oldroyd, G.E., Staskawicz, B.J., Rathjen, J.P. Plant Cell (2006) [Pubmed]
  4. The pattern visual-evoked potential in former preterm infants with retinopathy of prematurity. Mintz-Hittner, H.A., Prager, T.C., Schweitzer, F.C., Kretzer, F.L. Ophthalmology (1994) [Pubmed]
  5. The Hot Flash Related Daily Interference Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. Carpenter, J.S. Journal of pain and symptom management. (2001) [Pubmed]
  6. Creutzfeldt-Jakob disease: neurophysiologic visual impairments. de Seze, J., Hache, J.C., Vermersch, P., Arndt, C.F., Maurage, C.A., Pasquier, F., Laplanche, J.L., Ruchoux, M.M., Leys, D., Destée, A., Petit, H. Neurology (1998) [Pubmed]
  7. Flash P2 delay in primary degenerative dementia of the Alzheimer type. Moore, N.C., Tucker, K.A., Jann, M.W., Hostetler, R.M., Coburn, K.L. Prog. Neuropsychopharmacol. Biol. Psychiatry (1995) [Pubmed]
  8. The nematode death machine in 3D. Pop, C., Salvesen, G.S. Cell (2005) [Pubmed]
  9. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cecconi, F., Alvarez-Bolado, G., Meyer, B.I., Roth, K.A., Gruss, P. Cell (1998) [Pubmed]
  10. Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Yang, X., Chang, H.Y., Baltimore, D. Science (1998) [Pubmed]
  11. 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]
  12. Mutational analysis of the interacting cell death regulators CED-9 and CED-4. Ottilie, S., Wang, Y., Banks, S., Chang, J., Vigna, N.J., Weeks, S., Armstrong, R.C., Fritz, L.C., Oltersdorf, T. Cell Death Differ. (1997) [Pubmed]
  13. Structure and function of proteins controlling strain-specific pathogen resistance in plants. Ellis, J., Jones, D. Curr. Opin. Plant Biol. (1998) [Pubmed]
  14. Interaction and regulation of subcellular localization of CED-4 by CED-9. Wu, D., Wallen, H.D., Nuñez, G. Science (1997) [Pubmed]
  15. Apoptosomes: engines for caspase activation. Adams, J.M., Cory, S. Curr. Opin. Cell Biol. (2002) [Pubmed]
  16. Flash photolysis studies of excitation-contraction coupling, regulation, and contraction in smooth muscle. Somlyo, A.P., Somlyo, A.V. Annu. Rev. Physiol. (1990) [Pubmed]
  17. CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13. Fairlie, W.D., Perugini, M.A., Kvansakul, M., Chen, L., Huang, D.C., Colman, P.M. Cell Death Differ. (2006) [Pubmed]
  18. ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. Wilson, P.D., Hovater, J.S., Casey, C.C., Fortenberry, J.A., Schwiebert, E.M. J. Am. Soc. Nephrol. (1999) [Pubmed]
  19. The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. Huang, D.C., Adams, J.M., Cory, S. EMBO J. (1998) [Pubmed]
  20. Postsynaptic activation at the squid giant synapse by photolytic release of L-glutamate from a 'caged' L-glutamate. Corrie, J.E., DeSantis, A., Katayama, Y., Khodakhah, K., Messenger, J.B., Ogden, D.C., Trentham, D.R. J. Physiol. (Lond.) (1993) [Pubmed]
  21. Modulation of calcium current gating in frog skeletal muscle by conditioning depolarization. Feldmeyer, D., Melzer, W., Pohl, B., Zöllner, P. J. Physiol. (Lond.) (1992) [Pubmed]
  22. Evaluation of a rapid readout biological indicator for flash sterilization with three biological indicators and three chemical indicators. Rutala, W.A., Gergen, M.F., Weber, D.J. Infection control and hospital epidemiology : the official journal of the Society of Hospital Epidemiologists of America. (1993) [Pubmed]
  23. FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies. Milovic-Holm, K., Krieghoff, E., Jensen, K., Will, H., Hofmann, T.G. EMBO J. (2007) [Pubmed]
  24. WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. Hu, Y., Ding, L., Spencer, D.M., Núñez, G. J. Biol. Chem. (1998) [Pubmed]
  25. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Hu, Y., Benedict, M.A., Wu, D., Inohara, N., Núñez, G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. A comparison of the expression and properties of Apaf-1 and Apaf-1L. Walke, D.W., Morgan, J.I. Brain Res. (2000) [Pubmed]
  27. E1B 19,000-molecular-weight protein interacts with and inhibits CED-4-dependent, FLICE-mediated apoptosis. Han, J., Wallen, H.D., Nuñez, G., White, E. Mol. Cell. Biol. (1998) [Pubmed]
  28. Identification of a Bcl-XL binding region within the ATPase domain of Apaf-1. Yajima, H., Suzuki, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  29. Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis. Sadasivam, S., Gupta, S., Radha, V., Batta, K., Kundu, T.K., Swarup, G. Oncogene (2005) [Pubmed]
  30. Electroretinographic changes in eyes of patients with BRCA1 gene mutation. Lubiński, W., Górski, B., Szych, Z., Penkala, K., Palacz, O., Lubiński, J. Ophthalmic Res. (2003) [Pubmed]
  31. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Yan, N., Gu, L., Kokel, D., Chai, J., Li, W., Han, A., Chen, L., Xue, D., Shi, Y. Mol. Cell (2004) [Pubmed]
  32. Comparison of magnetic resonance imaging colonography with conventional colonoscopy for the assessment of intestinal inflammation in patients with inflammatory bowel disease: a feasibility study. Schreyer, A.G., Rath, H.C., Kikinis, R., Völk, M., Schölmerich, J., Feuerbach, S., Rogler, G., Seitz, J., Herfarth, H. Gut (2005) [Pubmed]
  33. Reliability of the comet assay in cryopreserved human sperm. Duty, S.M., Singh, N.P., Ryan, L., Chen, Z., Lewis, C., Huang, T., Hauser, R. Hum. Reprod. (2002) [Pubmed]
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