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Gene Review

Casp9  -  caspase 9

Mus musculus

Synonyms: AI115399, APAF-3, AW493809, Apoptotic protease Mch-6, Apoptotic protease-activating factor 3, ...
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Disease relevance of Casp9


Psychiatry related information on Casp9


High impact information on Casp9

  • Comparison of the requirement for Casp9 and Casp3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells [8].
  • Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9 [9].
  • Mutation of Caspase 9 (Casp9) results in embryonic lethality and defective brain development associated with decreased apoptosis [8].
  • Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not [1].
  • There are, however, mitochondrially regulated cell death pathways that are independent of Apaf1/caspase-9 [10].

Chemical compound and disease context of Casp9


Biological context of Casp9


Anatomical context of Casp9


Associations of Casp9 with chemical compounds


Physical interactions of Casp9

  • The mechanism underlying the shift is the result of a threefold compensatory elevation of caspase-9 expression and a doubling of levels of direct IAP binding protein with low pI/(DIABLO)/second mitochondria-derived activator of caspase (Smac), an IAP inhibitor, both at the mRNA and protein levels [corrected] [26].

Enzymatic interactions of Casp9

  • Activated Caspase-9 cleaves downstream caspases such as Caspase-3, -6 and -7 initiating the caspase cascade [22].
  • Recently, it was shown that human caspase-9 is phosphorylated by Akt and that its protease activity is reduced [27].
  • Immunoblot analysis revealed that the upstream caspases-8 and -9 are both activated in a time-dependent fashion, and caspase-8 is cleaved prior to caspase-9 [28].

Co-localisations of Casp9

  • Cleaved caspase-9 first appeared in the cytosol at 2 hours and colocalized with cytochrome c. Terminal deoxynucleotidyl transferase-mediated uridine 5;-triphosphate-biotin nick and labeling (TUNEL) showed significant increase of positive cells in Sod2 -/+ mice compared with the wild-type in the cortex, but not in the caudate putamen [29].

Regulatory relationships of Casp9


Other interactions of Casp9

  • We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome [31].
  • In addition to the death receptor-mediated pathway, TNF-induced apoptosis was further mediated by disruption of mitochondrial functions, characterized by release of cytochrome c and activation of caspase 9 [32].
  • Targeted disruption of bcl-x(L), an antiapoptotic bcl-2 gene family member, causes massive death of immature neurons in the developing nervous system whereas disruption of caspase-9, a proapoptotic caspase gene family member, leads to decreased neuronal apoptosis and neurodevelopmental abnormalities [33].
  • In total, these results indicate a transition from Caspase-9- to Bax- and Bcl-X(L)-mediated neuronal apoptosis [33].
  • To determine whether Bcl-X(L) and Caspase-9 interact in an obligate pathway of neuronal apoptosis, bcl-x/caspase-9 double homozygous mutants were generated [33].

Analytical, diagnostic and therapeutic context of Casp9


  1. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Marsden, V.S., O'Connor, L., O'Reilly, L.A., Silke, J., Metcalf, D., Ekert, P.G., Huang, D.C., Cecconi, F., Kuida, K., Tomaselli, K.J., Roy, S., Nicholson, D.W., Vaux, D.L., Bouillet, P., Adams, J.M., Strasser, A. Nature (2002) [Pubmed]
  2. The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. Inoue, H., Tsukita, K., Iwasato, T., Suzuki, Y., Tomioka, M., Tateno, M., Nagao, M., Kawata, A., Saido, T.C., Miura, M., Misawa, H., Itohara, S., Takahashi, R. EMBO J. (2003) [Pubmed]
  3. Regulation of the expression of caspase-9 by the transcription factor activator protein-4 in glucocorticoid-induced apoptosis. Tsujimoto, K., Ono, T., Sato, M., Nishida, T., Oguma, T., Tadakuma, T. J. Biol. Chem. (2005) [Pubmed]
  4. Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression. Haga, A., Funasaka, T., Niinaka, Y., Raz, A., Nagase, H. Int. J. Cancer (2003) [Pubmed]
  5. Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice. Oberholzer, C., Tschoeke, S.K., Moldawer, L.L., Oberholzer, A. J. Mol. Med. (2006) [Pubmed]
  6. Apoptotic signaling proteins: possible participation in the regulation of vasopressin and catecholamines biosynthesis in the hypothalamus. Chernigovskaya, E.V., Taranukhin, A.G., Glazova, M.V., Yamova, L.A., Fedorov, L.M. Histochem. Cell Biol. (2005) [Pubmed]
  7. Cytochrome C and caspase-9 expression in Huntington's disease. Kiechle, T., Dedeoglu, A., Kubilus, J., Kowall, N.W., Beal, M.F., Friedlander, R.M., Hersch, S.M., Ferrante, R.J. Neuromolecular Med. (2002) [Pubmed]
  8. Differential requirement for caspase 9 in apoptotic pathways in vivo. Hakem, R., Hakem, A., Duncan, G.S., Henderson, J.T., Woo, M., Soengas, M.S., Elia, A., de la Pompa, J.L., Kagi, D., Khoo, W., Potter, J., Yoshida, R., Kaufman, S.A., Lowe, S.W., Penninger, J.M., Mak, T.W. Cell (1998) [Pubmed]
  9. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Kuida, K., Haydar, T.F., Kuan, C.Y., Gu, Y., Taya, C., Karasuyama, H., Su, M.S., Rakic, P., Flavell, R.A. Cell (1998) [Pubmed]
  10. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Joza, N., Susin, S.A., Daugas, E., Stanford, W.L., Cho, S.K., Li, C.Y., Sasaki, T., Elia, A.J., Cheng, H.Y., Ravagnan, L., Ferri, K.F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.Y., Mak, T.W., Zúñiga-Pflücker, J.C., Kroemer, G., Penninger, J.M. Nature (2001) [Pubmed]
  11. Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. Viswanath, V., Wu, Y., Boonplueang, R., Chen, S., Stevenson, F.F., Yantiri, F., Yang, L., Beal, M.F., Andersen, J.K. J. Neurosci. (2001) [Pubmed]
  12. Teratogen-induced activation of caspase-9 and the mitochondrial apoptotic pathway in early postimplantation mouse embryos. Little, S.A., Mirkes, P.E. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  13. Involvement of mitochondrial permeability transition and caspase-9 activation in dimethyl sulfoxide-induced apoptosis of EL-4 lymphoma cells. Liu, J., Yoshikawa, H., Nakajima, Y., Tasaka, K. Int. Immunopharmacol. (2001) [Pubmed]
  14. Role of reactive oxygen species and spinal cord apoptotic genes in the development of neuropathic pain. Siniscalco, D., Fuccio, C., Giordano, C., Ferraraccio, F., Palazzo, E., Luongo, L., Rossi, F., Roth, K.A., Maione, S., de Novellis, V. Pharmacol. Res. (2007) [Pubmed]
  15. Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. Mueller, T., Voigt, W., Simon, H., Fruehauf, A., Bulankin, A., Grothey, A., Schmoll, H.J. Cancer Res. (2003) [Pubmed]
  16. Coupling of caspase-9 to Apaf1 in response to loss of pRb or cytotoxic drugs is cell-type-specific. Ho, A.T., Li, Q.H., Hakem, R., Mak, T.W., Zacksenhaus, E. EMBO J. (2004) [Pubmed]
  17. Regulation of caspase 9 through phosphorylation by protein kinase C zeta in response to hyperosmotic stress. Brady, S.C., Allan, L.A., Clarke, P.R. Mol. Cell. Biol. (2005) [Pubmed]
  18. DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3. D'Sa-Eipper, C., Leonard, J.R., Putcha, G., Zheng, T.S., Flavell, R.A., Rakic, P., Kuida, K., Roth, K.A. Development (2001) [Pubmed]
  19. Dimerization and processing of procaspase-9 by redox stress in mitochondria. Katoh, I., Tomimori, Y., Ikawa, Y., Kurata, S. J. Biol. Chem. (2004) [Pubmed]
  20. Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. Nakanishi, K., Maruyama, M., Shibata, T., Morishima, N. J. Biol. Chem. (2001) [Pubmed]
  21. HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. Lee, J.S., Lee, J.J., Seo, J.S. J. Biol. Chem. (2005) [Pubmed]
  22. Caspase-9. Kuida, K. Int. J. Biochem. Cell Biol. (2000) [Pubmed]
  23. Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro. Saintier, D., Khanine, V., Uzan, B., Ea, H.K., de Vernejoul, M.C., Cohen-Solal, M.E. J. Steroid Biochem. Mol. Biol. (2006) [Pubmed]
  24. Caspase-9 takes part in programmed cell death in developing mouse kidney. Araki, T., Hayashi, M., Nakanishi, K., Morishima, N., Saruta, T. Nephron Exp. Nephrol. (2003) [Pubmed]
  25. Taurine monochloramine activates a cell death pathway involving Bax and Caspase-9. Emerson, D.K., McCormick, M.L., Schmidt, J.A., Knudson, C.M. J. Biol. Chem. (2005) [Pubmed]
  26. Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. Troy, C.M., Rabacchi, S.A., Hohl, J.B., Angelastro, J.M., Greene, L.A., Shelanski, M.L. J. Neurosci. (2001) [Pubmed]
  27. Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Fujita, E., Jinbo, A., Matuzaki, H., Konishi, H., Kikkawa, U., Momoi, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  28. Expression of dominant-negative Fas-associated death domain blocks human keratinocyte apoptosis and vesication induced by sulfur mustard. Rosenthal, D.S., Velena, A., Chou, F.P., Schlegel, R., Ray, R., Benton, B., Anderson, D., Smith, W.J., Simbulan-Rosenthal, C.M. J. Biol. Chem. (2003) [Pubmed]
  29. Manganese Superoxide Dismutase Affects Cytochrome c Release and Caspase-9 Activation After Transient Focal Cerebral Ischemia in Mice. Noshita, N., Sugawara, T., Fujimura, M., Morita-Fujimura, Y., Chan, P.H. J. Cereb. Blood Flow Metab. (2001) [Pubmed]
  30. Caspase-8 in apoptosis: the beginning of "the end"? Kruidering, M., Evan, G.I. IUBMB Life (2000) [Pubmed]
  31. Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells. McDonnell, M.A., Wang, D., Khan, S.M., Vander Heiden, M.G., Kelekar, A. Cell Death Differ. (2003) [Pubmed]
  32. Tumor necrosis factor regulation of apoptosis in mouse preimplantation embryos and its antagonism by transforming growth factor alpha/phosphatidylionsitol 3-kinase signaling system. Kawamura, K., Kawamura, N., Kumagai, J., Fukuda, J., Tanaka, T. Biol. Reprod. (2007) [Pubmed]
  33. Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. Zaidi, A.U., D'Sa-Eipper, C., Brenner, J., Kuida, K., Zheng, T.S., Flavell, R.A., Rakic, P., Roth, K.A. J. Neurosci. (2001) [Pubmed]
  34. Genetic determinants that influence hypoxia-induced apoptosis. Alarcon, R.M., Denko, N.C., Giaccia, A.J. Novartis Found. Symp. (2001) [Pubmed]
  35. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Tu, S., McStay, G.P., Boucher, L.M., Mak, T., Beere, H.M., Green, D.R. Nat. Cell Biol. (2006) [Pubmed]
  36. Expression of apoptosis-related factors in muscles infected with Trichinella spiralis. Boonmars, T., Wu, Z., Nagano, I., Takahashi, Y. Parasitology (2004) [Pubmed]
  37. Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor- and Fas-mediated hepatocyte apoptosis in mice. Imao, M., Nagaki, M., Imose, M., Moriwaki, H. Liver Int. (2006) [Pubmed]
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