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Gene Review

Casp12  -  caspase 12

Mus musculus

Synonyms: CASP-12, Caspase-12
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Disease relevance of Casp12


High impact information on Casp12

  • Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta [4].
  • Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals [4].
  • Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis [5].
  • In a culture model, we demonstrate activation of caspase-12, the initiator of the endoplasmic reticulum (ER) stress-specific caspase cascade, during apoptosis associated with myoblast differentiation [6].
  • However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage [7].

Biological context of Casp12


Anatomical context of Casp12


Associations of Casp12 with chemical compounds


Physical interactions of Casp12


Regulatory relationships of Casp12


Other interactions of Casp12

  • Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity [2].
  • The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma receptors ablated the survival advantage that otherwise occurred in these animals [2].
  • This notion is confirmed by the observations that pretreatment of NIH3T3 cells with either caspase-12 antisense RNA or dsRNA corresponding to the full-length caspase-12 led to a dramatic decrease in caspase-3-like activity induced by Mn(II) [14].
  • These data suggest that procaspase-9 is a substrate of caspase-12 and that ER stress triggers a specific cascade involving caspase-12, -9, and -3 in a cytochrome c-independent manner [17].
  • We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage [3].

Analytical, diagnostic and therapeutic context of Casp12


  1. Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. Wootz, H., Hansson, I., Korhonen, L., Näpänkangas, U., Lindholm, D. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  2. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Saleh, M., Mathison, J.C., Wolinski, M.K., Bensinger, S.J., Fitzgerald, P., Droin, N., Ulevitch, R.J., Green, D.R., Nicholson, D.W. Nature (2006) [Pubmed]
  3. Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Shibata, M., Hattori, H., Sasaki, T., Gotoh, J., Hamada, J., Fukuuchi, Y. Neuroscience (2003) [Pubmed]
  4. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A., Yuan, J. Nature (2000) [Pubmed]
  5. GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Tessitore, A., del P Martin, M., Sano, R., Ma, Y., Mann, L., Ingrassia, A., Laywell, E.D., Steindler, D.A., Hendershot, L.M., d'Azzo, A. Mol. Cell (2004) [Pubmed]
  6. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. Nakanishi, K., Sudo, T., Morishima, N. J. Cell Biol. (2005) [Pubmed]
  7. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. Zong, W.X., Li, C., Hatzivassiliou, G., Lindsten, T., Yu, Q.C., Yuan, J., Thompson, C.B. J. Cell Biol. (2003) [Pubmed]
  8. Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. Obeng, E.A., Boise, L.H. J. Biol. Chem. (2005) [Pubmed]
  9. ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Jimbo, A., Fujita, E., Kouroku, Y., Ohnishi, J., Inohara, N., Kuida, K., Sakamaki, K., Yonehara, S., Momoi, T. Exp. Cell Res. (2003) [Pubmed]
  10. Caspase-12: a developmental link between G-protein-coupled receptors and integrin alphaIIbbeta3 activation. Kerrigan, S.W., Gaur, M., Murphy, R.P., Shattil, S.J., Leavitt, A.D. Blood (2004) [Pubmed]
  11. Regulation of the expression and processing of caspase-12. Kalai, M., Lamkanfi, M., Denecker, G., Boogmans, M., Lippens, S., Meeus, A., Declercq, W., Vandenabeele, P. J. Cell Biol. (2003) [Pubmed]
  12. Formation of noncanonical high molecular weight caspase-3 and -6 complexes and activation of caspase-12 during serum starvation induced apoptosis in AKR-2B mouse fibroblasts. Kilic, M., Schäfer, R., Hoppe, J., Kagerhuber, U. Cell Death Differ. (2002) [Pubmed]
  13. Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. Kouroku, Y., Fujita, E., Jimbo, A., Kikuchi, T., Yamagata, T., Momoi, M.Y., Kominami, E., Kuida, K., Sakamaki, K., Yonehara, S., Momoi, T. Hum. Mol. Genet. (2002) [Pubmed]
  14. Manganese(II) induces apoptotic cell death in NIH3T3 cells via a caspase-12-dependent pathway. Oubrahim, H., Chock, P.B., Stadtman, E.R. J. Biol. Chem. (2002) [Pubmed]
  15. Paracetamol-induced renal tubular injury: a role for ER stress. Lorz, C., Justo, P., Sanz, A., Subirá, D., Egido, J., Ortiz, A. J. Am. Soc. Nephrol. (2004) [Pubmed]
  16. XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice. Wootz, H., Hansson, I., Korhonen, L., Lindholm, D. Exp. Cell Res. (2006) [Pubmed]
  17. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. Morishima, N., Nakanishi, K., Takenouchi, H., Shibata, T., Yasuhiko, Y. J. Biol. Chem. (2002) [Pubmed]
  18. Molecular cloning and characterization of murine caspase-12 gene promoter. Oubrahim, H., Wang, J., Stadtman, E.R., Chock, P.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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