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Gene Review

Casp2  -  caspase 2

Rattus norvegicus

Synonyms: CASP-2, Caspase-2, Ich1, Protease ICH-1
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Disease relevance of Casp2

  • Taken together, the data suggest that caspase-2 induction and activation are important mediators of delayed neuronal death following transient global ischemia [1].
  • Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia [1].
  • After infection with Cre-producing recombinant adenovirus (re-Ad), the expression of caspase-2 was highly induced in PC-Nd cells and presumptive actively processed fragments of caspase-2 were also observed [2].
  • Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons [3].
  • CONCLUSION: In Cy/Cy kidneys with ADPKD, there was an increase of the proform of caspase-9, an increase in cytochrome c release into the cytosol, and an increase in caspase-2 protein and activity demonstrating involvement of the intrinsic pathway [4].

Psychiatry related information on Casp2

  • Changes in caspase-2 and -3 protein levels in Alzheimer's disease (AD) brains were assessed in comparison with their expression in development and aging [5].

High impact information on Casp2


Biological context of Casp2

  • Caspase-2, -3, -6 and -9 were activated during apoptosis and caspase-2 inhibitor (Z-VDVAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK) significantly attenuated the apoptosis [10].
  • Finally, intraventricular administration of the caspase-2-like inhibitor (VDVAD-FMK) 30 min before induction of ischemia decreased the number of CA1 neurons staining positively for DNA damage (Klenow-labeling assay) and increased the number of healthy-appearing CA1 neurons (cresyl violet) compared with vehicle-treated controls [1].
  • A rat ischemic brain cDNA library was screened, and two splice-variants of caspase-2 mRNA were identified, caspase-2S and caspase-2L, which were highly homologous with the sequences of human and mouse caspase-2S and caspase-2L genes, respectively [1].
  • Interestingly, expression of antisense caspase-2 RNA blocked the p55-IC-induced cell death in naive but not in neuronal PC12 cells, whereas the caspase-3-like specific inhibitor Ac-Asp-Glu-Val-Asp-aldehyde partially inhibited this death in neuronal but not in naive cells [11].
  • The rat caspase-2 cDNA clones have an open reading frame (ORF) of 452 amino acids (aa) [2].

Anatomical context of Casp2


Associations of Casp2 with chemical compounds

  • To further characterize the interplay between generation and removal of new cells, we studied the role of caspase 2 (Nedd 2) and 3 (CPP 32) on the basis of the high expression of these cysteine proteases in neurogenic regions [16].
  • The aa sequence QACRG containing the active Cys residue, that is necessary for the proteolytic activity of ICE/Ced-3 (caspase) family of proteases, is also conserved in rat caspase-2 [2].
  • Rat caspase-2 also has several Asp residues in the amino and carboxyl cleavage regions similar to other caspase family proteins [2].
  • Agents previously shown to inhibit caspase-3-like activation, such as bcl-2 and the Cdk inhibitor flavopiridol, also acted upstream of caspase-2 processing [17].
  • Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2 [18].

Regulatory relationships of Casp2

  • The general caspase inhibitors BAF and zVAD-FMK inhibited N-terminal caspase-2 processing [17].
  • TGF beta1-treatment induced the progressive proteolytic processing of caspase-2 (ICH-1L/Nedd-2), whereas caspase-1 itself did not show any cleavage from the precursor [19].

Other interactions of Casp2


Analytical, diagnostic and therapeutic context of Casp2

  • Induction of TUNEL staining and immunoreactivities for caspases-1 and -3 was greatly reduced with GDNF treatment, whereas the reduction of caspase-2 staining was only minimum [25].
  • Western blot analysis showed that active forms of caspase-1-like and caspase-2-like proteases were upregulated at P28, concurrent with the peak in TUNEL-positive cells [12].
  • We examined the role of caspase-2 in a model of focally evoked limbic seizures with continuous EEG recording [26].
  • The numbers of TUNEL- and caspase-2-positive cells were lower in the BDNF-treated group at 6 hours after reperfusion (P<0.01) [27].
  • In this paper, we report genetic fine-positioning and radiation hybrid mapping of caspase-2 in the rat [23].


  1. Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia. Jin, K., Nagayama, T., Mao, X., Kawaguchi, K., Hickey, R.W., Greenberg, D.A., Simon, R.P., Graham, S.H. J. Neurochem. (2002) [Pubmed]
  2. Cloning and expression of the cDNA encoding rat caspase-2. Sato, N., Milligan, C.E., Uchiyama, Y., Oppenheim, R.W. Gene (1997) [Pubmed]
  3. Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia. Singh, M., Savitz, S.I., Hoque, R., Gupta, G., Roth, S., Rosenbaum, P.S., Rosenbaum, D.M. J. Neurochem. (2001) [Pubmed]
  4. Pathways of caspase-mediated apoptosis in autosomal-dominant polycystic kidney disease (ADPKD). Tao, Y., Kim, J., Stanley, M., He, Z., Faubel, S., Schrier, R.W., Edelstein, C.L. Kidney Int. (2005) [Pubmed]
  5. Changes in caspase expression in Alzheimer's disease: comparison with development and aging. Shimohama, S., Tanino, H., Fujimoto, S. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  6. Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death. Vaudry, D., Rousselle, C., Basille, M., Falluel-Morel, A., Pamantung, T.F., Fontaine, M., Fournier, A., Vaudry, H., Gonzalez, B.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. RAIDD is required for apoptosis of PC12 cells and sympathetic neurons induced by trophic factor withdrawal. Wang, Q., Maniati, M., Jabado, O., Pavlaki, M., Troy, C.M., Greene, L.A., Stefanis, L. Cell Death Differ. (2006) [Pubmed]
  8. RAIDD aggregation facilitates apoptotic death of PC12 cells and sympathetic neurons. Jabado, O., Wang, Q., Rideout, H.J., Yeasmin, M., Guo, K.X., Vekrellis, K., Papantonis, S., Angelastro, J.M., Troy, C.M., Stefanis, L. Cell Death Differ. (2004) [Pubmed]
  9. A serine protease is involved in the initiation of DNA damage-induced apoptosis. de Bruin, E.C., Meersma, D., de Wilde, J., den Otter, I., Schipper, E.M., Medema, J.P., Peltenburg, L.T. Cell Death Differ. (2003) [Pubmed]
  10. Norepinephrine induces apoptosis in neonatal rat endothelial cells via down-regulation of Bcl-2 and activation of beta-adrenergic and caspase-2 pathways. Fu, Y.C., Chi, C.S., Yin, S.C., Hwang, B., Chiu, Y.T., Hsu, S.L. Cardiovasc. Res. (2004) [Pubmed]
  11. The intracellular domain of p55 tumor necrosis factor receptor induces apoptosis which requires different caspases in naive and neuronal PC12 cells. Haviv, R., Stein, R. J. Neurosci. Res. (1998) [Pubmed]
  12. Caspaselike proteases activated in apoptotic photoreceptors of Royal College of Surgeons rats. Katai, N., Kikuchi, T., Shibuki, H., Kuroiwa, S., Arai, J., Kurokawa, T., Yoshimura, N. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  13. Tumor necrosis factor-alpha-induced apoptosis in olfactory epithelium in vitro: possible roles of caspase 1 (ICE), caspase 2 (ICH-1), and caspase 3 (CPP32). Suzuki, Y., Farbman, A.I. Exp. Neurol. (2000) [Pubmed]
  14. 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]
  15. B cell apoptosis triggered by antigen receptor ligation proceeds via a novel caspase-dependent pathway. Chen, W., Wang, H.G., Srinivasula, S.M., Alnemri, E.S., Cooper, N.R. J. Immunol. (1999) [Pubmed]
  16. Caspase inhibition decreases cell death in regions of adult neurogenesis. Biebl, M., Winner, B., Winkler, J. Neuroreport (2005) [Pubmed]
  17. Caspase-2 (Nedd-2) processing and death of trophic factor-deprived PC12 cells and sympathetic neurons occur independently of caspase-3 (CPP32)-like activity. Stefanis, L., Troy, C.M., Qi, H., Shelanski, M.L., Greene, L.A. J. Neurosci. (1998) [Pubmed]
  18. Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. Schulz, J.B., Weller, M., Matthews, R.T., Heneka, M.T., Groscurth, P., Martinou, J.C., Lommatzsch, J., von Coelln, R., Wüllner, U., Löschmann, P.A., Beal, M.F., Dichgans, J., Klockgether, T. Cell Death Differ. (1998) [Pubmed]
  19. ICE-like protease (caspase) is involved in transforming growth factor beta1-mediated apoptosis in FaO rat hepatoma cell line. Choi, K.S., Lim, I.K., Brady, J.N., Kim, S.J. Hepatology (1998) [Pubmed]
  20. 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]
  21. Caspase activation pathways induced by staurosporine and low potassium: role of caspase-2. Caballero-Benítez, A., Morán, J. J. Neurosci. Res. (2003) [Pubmed]
  22. Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. Marques, C.A., Keil, U., Bonert, A., Steiner, B., Haass, C., Muller, W.E., Eckert, A. J. Biol. Chem. (2003) [Pubmed]
  23. Mapping of caspase-2 in the rat and its exclusion as a candidate gene for lymphopenia. Hornum, L., Rasmussen, S.B., Markholst, H. Mamm. Genome (1999) [Pubmed]
  24. Gene expression analysis of the rat testis after treatment with di(2-ethylhexyl) phthalate using cDNA microarray and real-time RT-PCR. Kijima, K., Toyosawa, K., Yasuba, M., Matsuoka, N., Adachi, T., Komiyama, M., Mori, C. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  25. Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Kitagawa, H., Hayashi, T., Mitsumoto, Y., Koga, N., Itoyama, Y., Abe, K. Stroke (1998) [Pubmed]
  26. Caspase-2 activation is redundant during seizure-induced neuronal death. Henshall, D.C., Skradski, S.L., Bonislawski, D.P., Lan, J.Q., Simon, R.P. J. Neurochem. (2001) [Pubmed]
  27. BDNF diminishes caspase-2 but not c-Jun immunoreactivity of neurons in retinal ganglion cell layer after transient ischemia. Kurokawa, T., Katai, N., Shibuki, H., Kuroiwa, S., Kurimoto, Y., Nakayama, C., Yoshimura, N. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
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