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CASP10  -  caspase 10, apoptosis-related cysteine...

Homo sapiens

Synonyms: ALPS2, Apoptotic protease Mch-4, CASP-10, Caspase-10, FAS-associated death domain protein interleukin-1B-converting enzyme 2, ...
 
 
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Disease relevance of CASP10

  • Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas [1].
  • In this study, to explore the possibility that mutation of this gene might be involved in the development of non-Hodgkin lymphoma (NHL), we have analyzed the entire coding region and all splice sites of the CASP10 gene for the detection of somatic mutations in 117 human NHLs [1].
  • Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant [2].
  • Variation in CASP10 gene is associated with idiopathic talipes equinovarus [3].
  • Expression of Mch4 in Escherichia coli produced an active protease that, like other ASCPs, was potently inhibited (Kj = 14 nM) by the tetrapeptide aldehyde DEVD-CHO [4].
 

High impact information on CASP10

  • This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA [5].
  • Like other ASCPs, the new proteases, named Mch4 and Mch5, are derived from single chain proenzymes [4].
  • Granzyme B also cleaves proMch4 at a homologous IXXD-A processing sequence to produce mature Mch4 [4].
  • A recent report described that inherited CASP10 gene mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome (ALPS) [1].
  • A strong PXR site was also predicted upstream of the CASP10 gene (18.69 bits at -7872) and was validated by binding studies and reporter assays as a PXR responsive element [6].
 

Biological context of CASP10

  • Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling [7].
  • A functional role for FLICE2 is suggested by the finding that an active site mutant of FLICE2 inhibits CD95 and tumor necrosis factor receptor-mediated apoptosis [7].
  • However, we did find evidence of downregulated gene expression in CFLAR, CASP10 and PPP1R7 in CC cell lines [8].
  • Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization [2].
  • Genotyping of SNPs throughout the genes in this sample of ITEV families has revealed positive linkage with association to the major allele of a variant in CASP10 in simplex ITEV white and Hispanic trios [3].
 

Anatomical context of CASP10

 

Associations of CASP10 with chemical compounds

  • Interestingly, both Mch4 and the serine protease granzyme B cleave recombinant proCPP32 and proMch3 at a conserved IXXD-S sequence to produce the large and small subunits of the active proteases [4].
  • The extrinsic pathway to apoptosis is not involved in drug-induced caspase-10 activation that occurs downstream of Bax redistribution to mitochondria and cytochrome c release from this organelle. siRNA-mediated downregulation of Apaf-1 prevents etoposide-mediated activation of caspase-10 [10].
 

Physical interactions of CASP10

  • We show that the pro-domain of FLICE2 encodes a functional death effector domain that binds to the corresponding domain in the adapter molecule FADD [7].
 

Regulatory relationships of CASP10

  • Importantly, the expression levels of GRB2 and FLICE2 genes were remarkably enhanced in RA synoviocytes but not in OA synoviocytes in response to tumor necrosis factor (TNF)-alpha treatment [9].
 

Other interactions of CASP10

  • Since the overall architecture and function of this molecule is similar to that of FLICE, it has been designated FLICE2 [7].
  • The intron-exon organizations of these genes as well as those of CFLAR, CASP10, and CASP8, which were previously mapped to this region, were defined [11].
  • Caspase-10/a (Mch4) and caspase-10/b (FLICE2) are related death effector domain-containing cysteine aspartases presumed to be at or near the apex of apoptotic signaling pathways [12].
  • Apoptosis-related genes CASP10 and MMP11 were overexpressed in SDC, in accordance with the typical tumor necrosis seen in this entity [13].
 

Analytical, diagnostic and therapeutic context of CASP10

  • We investigated the influence of the coding CASP10 variant V410I (G1228A) by performing a case-control study - using 511 familial BC cases and 547 control subjects - on BC risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43-0.88, P = 0.0076) related to the number of variant alleles (P(trend) = 0.0039) [2].

References

  1. Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas. Shin, M.S., Kim, H.S., Kang, C.S., Park, W.S., Kim, S.Y., Lee, S.N., Lee, J.H., Park, J.Y., Jang, J.J., Kim, C.W., Kim, S.H., Lee, J.Y., Yoo, N.J., Lee, S.H. Blood (2002) [Pubmed]
  2. Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant. Frank, B., Hemminki, K., Wappenschmidt, B., Meindl, A., Klaes, R., Schmutzler, R.K., Bugert, P., Untch, M., Bartram, C.R., Burwinkel, B. Carcinogenesis (2006) [Pubmed]
  3. Variation in CASP10 gene is associated with idiopathic talipes equinovarus. Heck, A.L., Bray, M.S., Scott, A., Blanton, S.H., Hecht, J.T. Journal of pediatric orthopedics. (2005) [Pubmed]
  4. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Fernandes-Alnemri, T., Armstrong, R.C., Krebs, J., Srinivasula, S.M., Wang, L., Bullrich, F., Fritz, L.C., Trapani, J.A., Tomaselli, K.J., Litwack, G., Alnemri, E.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  5. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., Litwack, G., Alnemri, E.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  6. Development and refinement of pregnane X receptor (PXR) DNA binding site model using information theory: insights into PXR-mediated gene regulation. Vyhlidal, C.A., Rogan, P.K., Leeder, J.S. J. Biol. Chem. (2004) [Pubmed]
  7. Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. Vincenz, C., Dixit, V.M. J. Biol. Chem. (1997) [Pubmed]
  8. Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression. Narayan, G., Pulido, H.A., Koul, S., Lu, X.Y., Harris, C.P., Yeh, Y.A., Vargas, H., Posso, H., Terry, M.B., Gissmann, L., Schneider, A., Mansukhani, M., Rao, P.H., Murty, V.V. Oncogene (2003) [Pubmed]
  9. Regulation of GRB2 and FLICE2 expression by TNF-alpha in rheumatoid synovium. Huh, S.J., Paik, D.J., Chung, H.S., Youn, J. Immunol. Lett. (2003) [Pubmed]
  10. Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells. Filomenko, R., Prévotat, L., Rébé, C., Cortier, M., Jeannin, J.F., Solary, E., Bettaieb, A. Oncogene (2006) [Pubmed]
  11. Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2. Hadano, S., Yanagisawa, Y., Skaug, J., Fichter, K., Nasir, J., Martindale, D., Koop, B.F., Scherer, S.W., Nicholson, D.W., Rouleau, G.A., Ikeda, J., Hayden, M.R. Genomics (2001) [Pubmed]
  12. Molecular cloning and characterization of two novel pro-apoptotic isoforms of caspase-10. Ng, P.W., Porter, A.G., Jänicke, R.U. J. Biol. Chem. (1999) [Pubmed]
  13. Characterization of gene expression in major types of salivary gland carcinomas with epithelial differentiation. Leivo, I., Jee, K.J., Heikinheimo, K., Laine, M., Ollila, J., Nagy, B., Knuutila, S. Cancer Genet. Cytogenet. (2005) [Pubmed]
 
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