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Gene Review

Casp3  -  caspase 3

Rattus norvegicus

Synonyms: Apopain, CASP-3, CPP-32, Caspase-3, Cpp32, ...
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Disease relevance of Casp3


High impact information on Casp3

  • The treatment with H2O2 increased the number of cells stained positive by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and induced formation of DNA ladder and activation of CPP32, suggesting that H2O2 induced apoptosis of cardiac myocytes [6].
  • We show here that at least one CPP32 (caspase-3)-like member of the caspase family becomes activated when rodent lens epithelial cells terminally differentiate into anucleate lens fibers in vivo, and that a peptide inhibitor of these proteases blocks the denucleation process in an in vitro model of lens fiber differentiation [7].
  • Bocaspartyl(OMe)-fluoromethylketone (BAF), a cell-permeable inhibitor of the ICE family of cysteine proteases, inhibited ICE and CPP32 (IC50 approximately 4 microM) in vitro and blocked Fas-mediated apoptosis in thymocytes (EC50 approximately 10 microM) [8].
  • Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage [9].
  • Inhibition of apoptosis by these compounds was strongly correlated with a decrease in CPP32-like caspase activity [2].

Chemical compound and disease context of Casp3


Biological context of Casp3

  • Transient transfection of PACAP into 293T human kidney cells and rat-1 fibroblasts triggered apoptosis at 24 h, which was at least in part prevented by an inhibitor of casp-3-like enzymes [14].
  • The activation of CPP32 and apoptotic cell death were inhibited by addition of Z-VAD-fmk, a universal inhibitor of ICE-like proteases [15].
  • Our data suggest that transcriptional activation of IRP could be one of the mechanisms involved in the apoptotic death of cerebellar granule neurons [16].
  • Further, the addition of exogenous C(2)-ceramide induced CPP32 activation and DNA fragmentation in all three culture systems [17].
  • Our results clearly demonstrate that cell death in the spinal cord occurs after posttranslational activation of caspases that follow, at least for caspase-3, initial upregulation of CASP3 mRNA levels [18].

Anatomical context of Casp3


Associations of Casp3 with chemical compounds

  • Caspase 1 (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2) and 8 (Mch5, FLICE) expression was examined using immunohistochemistry in the brains of rats and gerbils following systemic administration of kainic acid (KA) [22].
  • The site of action of these agents is upstream of the caspases, because the CPP32-like and Nedd-2-cleaving activities that are induced upon withdrawal of trophic support in PC12 cells are inhibited when AEBSF and TLCK are applied to the cells [23].
  • As a step toward identifying the caspase(s) involved, the effects of N-acetyl Tyr-Val-Ala-Asp x chloromethyl ketone (YVAD x cmk), an interleukin-1beta converting enzyme-preferring inhibitor, and N-acetyl Asp-Glu-Val-Asp x fluoromethyl ketone (DEVD x fmk), a CPP32-preferring inhibitor, were also evaluated [24].
  • In all three cell culture systems, the activation of caspase-3-like activity (CPP32) coincided with the increased formation of ceramide from sphingomyelin and the onset of DNA fragmentation [17].
  • Inhibitors of phosphatidylinositol 3-kinase (wortmannin and LY294002) also induced caspase-3 (CPP32) activation, increased ceramide formation, induced DNA fragmentation, and reduced cell viability [17].

Regulatory relationships of Casp3


Other interactions of Casp3

  • Northern blot analysis revealed a transient induction of Nedd2 mRNA 8 h after the ischemic insult (3.8-fold) and an increase in Yama/CPP32 mRNA 16 to 24 h after the insult (5.8-fold at 24 h), whereas the expression of Ice remained constant [27].
  • Northern blot analysis of total RNA samples indicated that gonadotropin-promoted follicular survival was associated with reduced ovarian expression of messenger RNAs encoding Ich-1 and CPP32 [19].
  • The Caenorhabditis elegans death susceptibility gene, ced-3, has a number of homologs in vertebrate species, including interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), Ich-1long, and CPP32 [19].
  • Expression of the antiapoptotic protein Bcl-2 and proapoptotic proteins ICE and CPP32 were measured by Western blots [20].
  • In the present study we have examined the temporal, spatial and cellular expression patterns of mRNAs for the highly inducible HSPs, HSP70 and HSP27, together with the apoptotic marker, caspase 3 (CPP32) in rat brain after systemic administration of kainate [28].

Analytical, diagnostic and therapeutic context of Casp3

  • RT-PCR products, when subcloned and sequenced, provided full-length cDNAs for ICE (1,209 bp) and CPP32 (786 bp) and partial cDNA products for Mch2 (561 bp) and Nedd2 (811 bp) [29].
  • In situ hybridization histochemistry reveals that this IRP mRNA is expressed in neuron-enriched regions of the developing and adult rat brain but is profoundly downregulated in the adult (compared with developing) brain [16].
  • The level of caspase-3 (CPP32) was increased in the cholinergic denervation group compared to control and hippocampal sympathetic ingrowth groups [30].
  • Lipids from normal rat plasma, IRP, trypanosomal homogenates, HVSG, and PVSG were also extracted and separated by thin-layer chromatography (minimum level of detection, 20 micrograms of trypanosomal phospholipid per sample) [31].
  • Apoptosis was detected by the cell death detection ELISA assay, CPP32/caspase-3 assay, and nucleosomal DNA laddering [25].


  1. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. Yakovlev, A.G., Knoblach, S.M., Fan, L., Fox, G.B., Goodnight, R., Faden, A.I. J. Neurosci. (1997) [Pubmed]
  2. Inhibition of transforming growth factor beta1-induced hepatoma cell apoptosis by liver tumor promoters: characterization of primary signaling events and effects on CPP32-like caspase activity. Buchmann, A., Willy, C., Buenemann, C.L., Stroh, C., Schmiechen, A., Schwarz, M. Cell Death Differ. (1999) [Pubmed]
  3. CPP32/CASPASE-3-like proteases in hypoxia-induced apoptosis in developing brain neurons. Bossenmeyer-Pourié, C., Koziel, V., Daval, J.L. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  4. Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. Chaudhary, P., Ahmed, F., Quebada, P., Sharma, S.C. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  5. Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. Chen, J., Nagayama, T., Jin, K., Stetler, R.A., Zhu, R.L., Graham, S.H., Simon, R.P. J. Neurosci. (1998) [Pubmed]
  6. Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. Aikawa, R., Komuro, I., Yamazaki, T., Zou, Y., Kudoh, S., Tanaka, M., Shiojima, I., Hiroi, Y., Yazaki, Y. J. Clin. Invest. (1997) [Pubmed]
  7. A role for caspases in lens fiber differentiation. Ishizaki, Y., Jacobson, M.D., Raff, M.C. J. Cell Biol. (1998) [Pubmed]
  8. Genetic and metabolic status of NGF-deprived sympathetic neurons saved by an inhibitor of ICE family proteases. Deshmukh, M., Vasilakos, J., Deckwerth, T.L., Lampe, P.A., Shivers, B.D., Johnson, E.M. J. Cell Biol. (1996) [Pubmed]
  9. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Hara, H., Friedlander, R.M., Gagliardini, V., Ayata, C., Fink, K., Huang, Z., Shimizu-Sasamata, M., Yuan, J., Moskowitz, M.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Thyrotropin-releasing hormone and epidermal growth factor regulate iron-regulatory protein binding in pituitary cells via protein kinase C-dependent and -independent signaling pathways. Thomson, A.M., Rogers, J.T., Leedman, P.J. J. Biol. Chem. (2000) [Pubmed]
  11. Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. Black, S.C., Huang, J.Q., Rezaiefar, P., Radinovic, S., Eberhart, A., Nicholson, D.W., Rodger, I.W. J. Mol. Cell. Cardiol. (1998) [Pubmed]
  12. Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Gillardon, F., Böttiger, B., Schmitz, B., Zimmermann, M., Hossmann, K.A. Brain Res. Mol. Brain Res. (1997) [Pubmed]
  13. Effect of nilvadipine on the cerebral ischemia-induced impairment of spatial memory and hippocampal apoptosis in rats. Iwasaki, K., Mishima, K., Egashira, N., Al-Khatib, I.H., Ishibashi, D., Irie, K., Kobayashi, H., Egawa, T., Fujiwara, M. J. Pharmacol. Sci. (2003) [Pubmed]
  14. Characterization of a novel proapoptotic caspase-2- and caspase-9-binding protein. Bonfoco, E., Li, E., Kolbinger, F., Cooper, N.R. J. Biol. Chem. (2001) [Pubmed]
  15. Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. Kangas, A., Nicholson, D.W., Hölttä, E. Oncogene (1998) [Pubmed]
  16. Cloning and expression of a rat brain interleukin-1beta-converting enzyme (ICE)-related protease (IRP) and its possible role in apoptosis of cultured cerebellar granule neurons. Ni, B., Wu, X., Du, Y., Su, Y., Hamilton-Byrd, E., Rockey, P.K., Rosteck, P., Poirier, G.G., Paul, S.M. J. Neurosci. (1997) [Pubmed]
  17. Differential responses of oligodendrocytes to tumor necrosis factor and other pro-apoptotic agents: role of ceramide in apoptosis. Scurlock, B., Dawson, G. J. Neurosci. Res. (1999) [Pubmed]
  18. Rapid upregulation of caspase-3 in rat spinal cord after injury: mRNA, protein, and cellular localization correlates with apoptotic cell death. Citron, B.A., Arnold, P.M., Sebastian, C., Qin, F., Malladi, S., Ameenuddin, S., Landis, M.E., Festoff, B.W. Exp. Neurol. (2000) [Pubmed]
  19. Interleukin-1 beta-converting enzyme-related proteases (IRPs) and mammalian cell death: dissociation of IRP-induced oligonucleosomal endonuclease activity from morphological apoptosis in granulosa cells of the ovarian follicle. Flaws, J.A., Kugu, K., Trbovich, A.M., DeSanti, A., Tilly, K.I., Hirshfield, A.N., Tilly, J.L. Endocrinology (1995) [Pubmed]
  20. Impaired apoptotic death signaling in inflammatory lung neutrophils is associated with decreased expression of interleukin-1 beta converting enzyme family proteases (caspases). Watson, R.W., Rotstein, O.D., Parodo, J., Jimenez, M., Soric, I., Bitar, R., Marshall, J.C. Surgery (1997) [Pubmed]
  21. Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. Kermer, P., Klöcker, N., Labes, M., Bähr, M. J. Neurosci. (1998) [Pubmed]
  22. Differential c-Fos and caspase expression following kainic acid excitotoxicity. Ferrer, I., López, E., Blanco, R., Rivera, R., Krupinski, J., Martí, E. Acta Neuropathol. (2000) [Pubmed]
  23. Inhibitors of trypsin-like serine proteases inhibit processing of the caspase Nedd-2 and protect PC12 cells and sympathetic neurons from death evoked by withdrawal of trophic support. Stefanis, L., Troy, C.M., Qi, H., Greene, L.A. J. Neurochem. (1997) [Pubmed]
  24. A DEVD-inhibited caspase other than CPP32 is involved in the commitment of cerebellar granule neurons to apoptosis induced by K+ deprivation. D'Mello, S.R., Aglieco, F., Roberts, M.R., Borodezt, K., Haycock, J.W. J. Neurochem. (1998) [Pubmed]
  25. Smad7 mediates transforming growth factor-beta-induced apoptosis in mesangial cells. Okado, T., Terada, Y., Tanaka, H., Inoshita, S., Nakao, A., Sasaki, S. Kidney Int. (2002) [Pubmed]
  26. Processing/activation of CPP32-like proteases is involved in transforming growth factor beta1-induced apoptosis in rat hepatocytes. Inayat-Hussain, S.H., Couet, C., Cohen, G.M., Cain, K. Hepatology (1997) [Pubmed]
  27. Expression of interleukin-1 beta converting enzyme gene family and bcl-2 gene family in the rat brain following permanent occlusion of the middle cerebral artery. Asahi, M., Hoshimaru, M., Uemura, Y., Tokime, T., Kojima, M., Ohtsuka, T., Matsuura, N., Aoki, T., Shibahara, K., Kikuchi, H. J. Cereb. Blood Flow Metab. (1997) [Pubmed]
  28. Heat shock protein 27 shows a distinctive widespread spatial and temporal pattern of induction in CNS glial and neuronal cells compared to heat shock protein 70 and caspase 3 following kainate administration. Akbar, M.T., Wells, D.J., Latchman, D.S., de Belleroche, J. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  29. Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. Kaushal, G.P., Singh, A.B., Shah, S.V. Am. J. Physiol. (1998) [Pubmed]
  30. Apoptotic protein expression and activation of caspases is changed following cholinergic denervation and hippocampal sympathetic ingrowth in rat hippocampus. Kolasa, K., Harrell, L.E. Neuroscience (2000) [Pubmed]
  31. Biochemical and immunological characterization of the variant surface coat glycoprotein shed by African trypanosomes. Diffley, P., Straus, D.C. Infect. Immun. (1986) [Pubmed]
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