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Gene Review

CASP4  -  caspase 4, apoptosis-related cysteine...

Homo sapiens

Synonyms: CASP-4, Caspase-4, ICE(rel)-II, ICE(rel)II, ICEREL-II, ...
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Disease relevance of CASP4

  • Although additional studies are needed to define the molecular basis of the TX-LND interaction, our results suggest that LND can positively modulate the antitumor activity of TX in ovarian cancer cells and indicate that the energolytic is potentially useful in combination therapy including the taxane in ovarian cancer patients [1].

High impact information on CASP4

  • Confocal microscopy demonstrated that the TX-insoluble compartment is perinuclear and co-localizes with endoplasmic reticulum (ER) markers [2].
  • Transfection experiments demonstrate that TX is a protease which is able to cleave itself and the p30 ICE precursor, but not to generate mature IL-1 beta from pro-IL-1 beta [3].
  • TX therefore delineates a new member of the growing Ice/ced-3 gene family coding for proteases with cytokine processing activity or involved in programmed cell death [3].
  • This model suggests that TX is a cysteine protease, with the P1 aspartic acid substrate specificity retained [3].
  • We report the identification of ICH-2, a novel human gene encoding a member of the ICE cysteine protease family, and characterization of its protein product [4].

Chemical compound and disease context of CASP4

  • The ability of lonidamine (LND), an energolytic derivative of indazole-carboxylic acid, to modulate the cytotoxicity of Taxol (TX) was investigated in the A2780 human ovarian cancer cell line [1].

Biological context of CASP4

  • Ranking of structures with the best scoring functions is compared across CASP4 targets to establish when physical scoring functions can be expected to reliably distinguish structures that are most similar to the native fold in a set of misfolded or unfolded protein conformations [5].
  • TX induced an oligonucleosomal DNA fragmentation typical of the apoptotic process [1].
  • This combined method was used to make predictions for 28 protein domains in the Critical Assessment of Protein Structure 4 (CASP 4) and 59 domains in CASP 5, where the method ranked highly among comparative modeling and fold recognition methods [6].
  • The nature of the calcium binding sites in the TX peptide and native salivary proteins A and C, as well as dephosphorylated proteins were compared [7].
  • However, only 22% (23/103) and 40% (59/149) of examined metaphases were scored as normal in TX + DTT or ATAB + DTT treatments, respectively [8].

Anatomical context of CASP4

  • In addition, as already observed for ICE and TX, TY is able to induce apoptosis when overexpressed in COS cells [9].
  • Here, we present a model that describes the process of domain formation in membranes in the presence and in the absence of TX [10].
  • Spermatozoa were treated with vigorous pipetting to induce membrane disruption or with TX or the ionic detergent mixed alkyltrimethylammonium bromide (ATAB) [8].
  • TX-treated spermatozoa still had their entire DNA associated with the nuclear matrix, even though the DNA was digested into 50-kb fragments as revealed by PFGE [11].

Associations of CASP4 with chemical compounds

  • All the calcium-binding sites are located in the NH2-terminal tryptic peptide (TX peptide) [7].
  • We measure the interactions between TX and an equimolar mixture of sphingomyelin (SM), cholesterol (Cho), and 1-palmitoyl-2-oleoyl-3-sn-glycero-phosphatidylcholine (POPC) (1:1:1, mol) by means of isothermal titration calorimetry [10].
  • Comparison with pure POPC membranes reveals a very unfavorable interaction between TX and SM/Cho, which causes a substantial tendency to segregate these molecules into separate, DRM-like (SM-rich) and fluid (TX-rich), domains [10].
  • The ceramide moieties of the GM1s determined their occurrence in DRMs and the dependence of their recovery in this membrane fraction on the amount of Triton X-100 (TX) used for extraction as well as on cholesterol depletion [12].
  • Ca2+ titration and pH-dependent measurements on protein A, the TX peptide, and the dephosphorylated TX peptide established the importance of the two phosphoserine residues in the binding of Ca2+ [13].

Other interactions of CASP4

  • There is a small barely detectable improvement between CASP3 and the latest experiment (CASP4, 2000) [14].
  • Predictive accuracies of 80.7% and 81.7% are achieved on the CASP4 and CASP5 targets, respectively [15].
  • Although clear progress has been made in improving FRAGFOLD since CASP4, the ranking of final models still seems to be the main problem that needs to be addressed before the next CASP experiment [16].
  • LND did not appreciably modify the effect exerted by TX on proteins involved in cell cycle progression (i.e., inhibition of p34cdc2 expression) and apoptosis (i.e., upregulation of wt p53 and transactivation of p21waf1), and only caused a slight induction of the Bax protein [1].
  • Additionally, under-expressed genes encoded apoptosis-related proteins (PDCD4 and CASP4) [17].
  • LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4 [18].

Analytical, diagnostic and therapeutic context of CASP4

  • Active ICE, TX and TY were collected in the cell culture supernatants [19].
  • DRMs prepared with low TX concentration at the TX/cell protein ratio of 0.3:1 were separated by multistep sucrose density gradient centrifugation into two fractions [12].
  • We found that the numbers of normal paternal karyoplates resulting from ICSI with spermatozoa treated with either DTT (87%, 153/176), TX (79%, 112/142), or ATAB (85%, 99/116) alone were similar to swim-up controls (92%, 103/112) [8].
  • Sequences were identified using genomic Southern-blot analysis of human DNA with probes corresponding to ICE and TX exon 6 [20].
  • Stable LHCII crystals were formed in the media containing Triton X-100 (TX) or n-nonyl-beta-D-glucopyranoside (NG) and the crystallization efficients were dependent on their concentrations [21].


  1. Lonidamine as a modulator of taxol activity in human ovarian cancer cells: effects on cell cycle and induction of apoptosis. Orlandi, L., Zaffaroni, N., Bearzatto, A., Villa, R., De Marco, C., Silvestrini, R. Int. J. Cancer (1998) [Pubmed]
  2. TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. Wu, C.J., Conze, D.B., Li, X., Ying, S.X., Hanover, J.A., Ashwell, J.D. EMBO J. (2005) [Pubmed]
  3. A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells. Faucheu, C., Diu, A., Chan, A.W., Blanchet, A.M., Miossec, C., Hervé, F., Collard-Dutilleul, V., Gu, Y., Aldape, R.A., Lippke, J.A. EMBO J. (1995) [Pubmed]
  4. Identification and characterization of ICH-2, a novel member of the interleukin-1 beta-converting enzyme family of cysteine proteases. Kamens, J., Paskind, M., Hugunin, M., Talanian, R.V., Allen, H., Banach, D., Bump, N., Hackett, M., Johnston, C.G., Li, P. J. Biol. Chem. (1995) [Pubmed]
  5. Evaluating CASP4 predictions with physical energy functions. Feig, M., Brooks, C.L. Proteins (2002) [Pubmed]
  6. Modeling structurally variable regions in homologous proteins with rosetta. Rohl, C.A., Strauss, C.E., Chivian, D., Baker, D. Proteins (2004) [Pubmed]
  7. The location and nature of calcium-binding sites in salivary acidic proline-rich phosphoproteins. Bennick, A., McLaughlin, A.C., Grey, A.A., Madapallimattam, G. J. Biol. Chem. (1981) [Pubmed]
  8. Combination of dithiothreitol and detergent treatment of spermatozoa causes paternal chromosomal damage. Szczygiel, M.A., Ward, W.S. Biol. Reprod. (2002) [Pubmed]
  9. Identification of a cysteine protease closely related to interleukin-1 beta-converting enzyme. Faucheu, C., Blanchet, A.M., Collard-Dutilleul, V., Lalanne, J.L., Diu-Hercend, A. Eur. J. Biochem. (1996) [Pubmed]
  10. The sensitivity of lipid domains to small perturbations demonstrated by the effect of Triton. Heerklotz, H., Szadkowska, H., Anderson, T., Seelig, J. J. Mol. Biol. (2003) [Pubmed]
  11. Ability of hamster spermatozoa to digest their own DNA. Sotolongo, B., Lino, E., Ward, W.S. Biol. Reprod. (2003) [Pubmed]
  12. Structure of the ceramide moiety of GM1 ganglioside determines its occurrence in different detergent-resistant membrane domains in HL-60 cells. Panasiewicz, M., Domek, H., Hoser, G., Kawalec, M., Pacuszka, T. Biochemistry (2003) [Pubmed]
  13. A calcium-43 NMR study of calcium binding to an acidic proline-rich phosphoprotein from human saliva. Braunlin, W.H., Vogel, H.J., Drakenberg, T., Bennick, A. Biochemistry (1986) [Pubmed]
  14. Comparison of performance in successive CASP experiments. Venclovas, C., Zemla, A., Fidelis, K., Moult, J. Proteins (2001) [Pubmed]
  15. Protein secondary structure prediction with dihedral angles. Wood, M.J., Hirst, J.D. Proteins (2005) [Pubmed]
  16. Assembling novel protein folds from super-secondary structural fragments. Jones, D.T., McGuffin, L.J. Proteins (2003) [Pubmed]
  17. Potential markers of tongue tumor progression selected by cDNA microarray. Carinci, F., Lo Muzio, L., Piattelli, A., Rubini, C., Chiesa, F., Ionna, F., Palmieri, A., Maiorano, E., Pastore, A., Laino, G., Dolci, M., Pezzetti, F. International journal of immunopathology and pharmacology. (2005) [Pubmed]
  18. Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-kappaB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1 ). Lakshmanan, U., Porter, A.G. J. Immunol. (2007) [Pubmed]
  19. Enzymatic activity of two caspases related to interleukin-1beta-converting enzyme. Fassy, F., Krebs, O., Rey, H., Komara, B., Gillard, C., Capdevila, C., Yea, C., Faucheu, C., Blanchet, A.M., Miossec, C., Diu-Hercend, A. Eur. J. Biochem. (1998) [Pubmed]
  20. Identification of five new genes, closely related to the interleukin-1beta converting enzyme gene, that do not encode functional proteases. Rocher, C., Faucheu, C., Blanchet, A.M., Claudon, M., Hervé, F., Durand, L., Harnois, M., Diu-Hercend, A., Lalanne, J.L. Eur. J. Biochem. (1997) [Pubmed]
  21. Detergent effects on the light-harvesting chlorophyll A/B-protein complex crystallization revealed by fluorescence depolarization. Furuichi, M., Nishimoto, E., Koga, T., Takase, A., Yamashita, S. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
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