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Gene Review

CASP6  -  caspase 6, apoptosis-related cysteine...

Homo sapiens

Synonyms: Apoptotic protease Mch-2, CASP-6, Caspase-6, MCH2
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Disease relevance of CASP6

  • This is the first report on CASP6 gene mutations in human cancers, and these data indicate that the CASP6 gene is occasionally mutated in gastric and colorectal carcinomas [1].
  • Mutational analysis of the CASP6 gene in colorectal and gastric carcinomas [1].
  • Employing the degenerate primer-dependent polymerase chain reaction approach used recently to clone human Mch2, we have identified and cloned the insect Spodoptera frugiperda target of the baculovirus antiapoptotic protein p35 [2].

High impact information on CASP6

  • Using tumor cells as a model, we have found that CPP32 (caspase 3) and Mch2 (caspase 6) are the major active caspases in apoptotic cells, and are activated in response to distinct apoptosis-inducing stimuli and in all cell lines analyzed [3].
  • Based on site-directed mutagenesis studies, 5-LO is cleaved by casp-6 after Asp-170, which in a homology-based 3D model of 5-LO is located on the enzyme periphery [4].
  • In parallel, splitting of BL41-E95-A cells induced activation of caspase-6 (casp-6) and casp-8 [4].
  • Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis [5].
  • We have shown recently that the CPP32 and Mch2 alpha cysteine proteases cleave the apoptotic markers poly(ADP-ribose) polymerase (PARP) and lamins, respectively [6].

Biological context of CASP6

  • Overall, we detected three somatic mutations of the CASP6 gene, including two missense mutations and one splice-site mutation [1].
  • Activation of casp-6 and casp-8 was connected to subsequent enhancement of cell proliferation, whereas selective caspase inhibition blocked cell growth [4].
  • The Sixth Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP6) held in December 2004 focused on the prediction of the structures of 90 protein domains from 64 targets [7].
  • BACKGROUND: Due to the functional importance of intrinsically disordered proteins or protein regions, prediction of intrinsic protein disorder from amino acid sequence has become an area of active research as witnessed in the 6th experiment on Critical Assessment of Techniques for Protein Structure Prediction (CASP6) [8].
  • First, we compared the substrate specificities of two recombinant human IRPs, CPP32 and Mch2 alpha [5].

Anatomical context of CASP6

  • However, the species of CPP32 and Mch2 detected varied between cell lines, indicating differences in caspase processing [3].
  • Here, we show that Mch2 is processed from its zymogen form to a proteolytically active dimeric species during execution of the apoptotic program and by the cytotoxic T cell death protease granzyme B [9].

Associations of CASP6 with chemical compounds


Enzymatic interactions of CASP6


Other interactions of CASP6

  • We suggest that splitting of BL41-E95-A cells induces de novo synthesis of a protein involved in the activation of casp-6, which cleaves 5-LO [4].
  • Of note, one colorectal carcinoma with the CASP6 mutation harbored CASP3 and CASP8 gene mutations as well [1].
  • CMH-1 has the highest similarity to CPP32 (52% amino acid identity) and MCH2 (31% identical) [10].
  • To explore the possibility that the genetic alterations of CASP, which encodes caspase-6, might be involved in the development of human cancers, we analyzed the entire coding region and all splice sites of the human CASP6 gene for the detection of somatic mutations in 100 colorectal carcinomas and 50 gastric carcinomas [1].
  • Here we report the chromosomal mapping of CPP32 to 4q34, MCH2 to 4q25, and MCH3 to 10q25 [11].


  1. Mutational analysis of the CASP6 gene in colorectal and gastric carcinomas. Lee, J.W., Kim, M.R., Soung, Y.H., Nam, S.W., Kim, S.H., Lee, J.Y., Yoo, N.J., Lee, S.H. APMIS (2006) [Pubmed]
  2. Spodoptera frugiperda caspase-1, a novel insect death protease that cleaves the nuclear immunophilin FKBP46, is the target of the baculovirus antiapoptotic protein p35. Ahmad, M., Srinivasula, S.M., Wang, L., Litwack, G., Fernandes-Alnemri, T., Alnemri, E.S. J. Biol. Chem. (1997) [Pubmed]
  3. Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells. Faleiro, L., Kobayashi, R., Fearnhead, H., Lazebnik, Y. EMBO J. (1997) [Pubmed]
  4. Caspase-mediated degradation of human 5-lipoxygenase in B lymphocytic cells. Werz, O., Tretiakova, I., Michel, A., Ulke-Lemee, A., Hörnig, M., Franke, L., Schneider, G., Samuelsson, B., Rådmark, O., Steinhilber, D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Takahashi, A., Alnemri, E.S., Lazebnik, Y.A., Fernandes-Alnemri, T., Litwack, G., Moir, R.D., Goldman, R.D., Poirier, G.G., Kaufmann, S.H., Earnshaw, W.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  6. Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Fernandes-Alnemri, T., Takahashi, A., Armstrong, R., Krebs, J., Fritz, L., Tomaselli, K.J., Wang, L., Yu, Z., Croce, C.M., Salveson, G. Cancer Res. (1995) [Pubmed]
  7. Assessment of fold recognition predictions in CASP6. Wang, G., Jin, Y., Dunbrack, R.L. Proteins (2005) [Pubmed]
  8. Length-dependent prediction of protein intrinsic disorder. Peng, K., Radivojac, P., Vucetic, S., Dunker, A.K., Obradovic, Z. BMC Bioinformatics (2006) [Pubmed]
  9. The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. Orth, K., Chinnaiyan, A.M., Garg, M., Froelich, C.J., Dixit, V.M. J. Biol. Chem. (1996) [Pubmed]
  10. Identification and characterization of CPP32/Mch2 homolog 1, a novel cysteine protease similar to CPP32. Lippke, J.A., Gu, Y., Sarnecki, C., Caron, P.R., Su, M.S. J. Biol. Chem. (1996) [Pubmed]
  11. Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3. Bullrich, F., Fernandes-Alnemri, T., Litwack, G., Alnemri, E.S., Croce, C.M. Genomics (1996) [Pubmed]
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