Disease relevance of Casp9

• Mammalian caspase-9 and its activator Apaf-1 were thought to be essential, because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli [1].
• The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model [2].
• When the cells were treated with dexamethasone, a rapid down-regulation of AP-4 and Casp-9 was observed whether the cells were GC-sensitive lymphomas or GC-insensitive L929 fibroblast cells [3].
• The disappearance of the Apaf-1 and Caspase-9 gene was recovered by a cellular signaling inhibitor of protein kinase C, phosphatidylinositol 3-phosphate kinase and mitogen-activated protein kinase of the in vitro cultured human fibrosarcoma HT-1080 line [4].
• Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice [5].

Psychiatry related information on Casp9

• Recently, we have shown that water deprivation leads to the activation of vasopressin (VP) secretion and expression of Bcl-2 and caspase-9 apototic proteins in the hypothalamus of the rat brain [6].
• Cytochrome C and caspase-9 expression in Huntington's disease [7].

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

• 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 [11].
• Herein we show that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine also activate caspase-9, the apical caspase in the mitochondrial apoptotic pathway [12].
• Involvement of mitochondrial permeability transition and caspase-9 activation in dimethyl sulfoxide-induced apoptosis of EL-4 lymphoma cells [13].
• Administration of phenyl-N-tert-butylnitrone (PBN), a potent ROS scavenger, reduced the development of thermal hyperalgesia and mechanical allodynia at 1 and 3 days post-CCI, and decreased the mRNA levels of bax, apaf-1, and caspase-9 [14].
• Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer [15].

Biological context of Casp9

• In addition, developmental cell death in fetal liver and PNS was not inhibited in Casp9(-/-) embryos [16].
• These results indicate that phosphorylation and inhibition of caspase 9 by PKCzeta restrain the intrinsic apoptotic pathway during hyperosmotic stress [17].
• The apoptotic pathway regulating DNA damage-induced neural precursor cell death is different from that required for normal brain morphogenesis, which involves both caspase 9 and caspase 3 but not p53, indicating that additional apoptotic stimuli regulate neural precursor cell numbers during telencephalic development [18].
• We studied the mechanism of intra-mitochondrial death initiator caspase-9 activation by a redox response, in which hydrogen peroxide (H(2)O(2)) caused a subtle decrease in the inner membrane potential (Deltapsim) with little evidence of cytochrome c release [19].
• Caspase-9 is an upstream caspase that can become active in response to cellular damage, including deprivation of growth factors and exposure to oxidative stress in vitro [20].

Anatomical context of Casp9

• Processing of procaspase-9 occurred in Apaf1(-/-) myoblasts but not fibroblasts, and ablation of Casp9 prevented drug-induced apoptosis in both cell types [16].
• Despite its requirement for apoptosis in vitro, mutation in Casp9 abrogated cell death in the nervous system and lens but only partly in skeletal muscles of Rb-deficient embryos [16].
• Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects [2].
• Intriguingly, disulfide-bonded dimers of autoprocessed caspase-9 were generated in the mitochondria in the pre-apoptotic phase [19].
• Caspase-9 and caspase-3 were rapidly activated, and extensive cleavage occurred in focal adhesion and cytoskeletal molecules in the hsp70.1-/-MEFs [21].

Associations of Casp9 with chemical compounds

• Phosphorylation of serine 144 in cells is also induced by hyperosmotic stress, which activates PKCzeta and regulates its interaction with caspase 9, but not by growth factors, phorbol ester, or other cellular stresses [17].
• Caspase-9 is a member of caspase family of cysteine proteases that have been implicated in apoptosis and cytokine processing [22].
• However, increased caspase-3 activity by estradiol was observed in the presence of caspase-9 inhibitor, indicating the preferential involvement of caspase-8 pathway [23].
• Administration of a caspase-9 inhibitor (Ac-IETD-CHO) effectively prevented both ureteric bud branching and nephrogenesis, the same as a caspase-3 inhibitor (Ac-DEVD-CHO) [24].
• Taurine monochloramine activates a cell death pathway involving Bax and Caspase-9 [25].

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

• Prevention of Ser144 phosphorylation by inhibition of PKCzeta or mutation of caspase 9 promotes caspase 3 activation [17].
• Caspase-9 (Casp-9) induces death signals by triggering other types of caspase activation, and its expression greatly influences the onset of apoptosis [3].
• In contrast, both the expression and activation of Casp-9 were inhibited in the antisense AP-4 transfectants [3].
• Mouse caspase-9 was not phosphorylated by activated Akt in vitro [27].
• Activated caspase-9 then activates further "downstream caspases," including caspase-8 [30].

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

• Here we test the hypothesis that Caspase 9 (Casp9) is a critical upstream activator of caspases through gene targeting in mice [9].
• Comparison of cell lines genetically matched at the bax, cytochrome c, apaf, caspase 9 and caspase 3 loci indicated that except for bax, all of these genes were essential for hypoxia induced apoptosis both in cell culture and in transplanted tumours [34].
• As expected, only caspase-8 was trapped in response to ligation of death receptors, whereas only caspase-9 was trapped in response to a variety of other apoptosis-inducing agents [35].
• Immunocytochemistry revealed that pro-apoptosis factor (BAX, Apaf-1 and Caspase 9) are predominantly expressed in the basophilic cytoplasm (infected muscle cell origin) and anti-apoptosis factor (PKB) in the eosinophilic cytoplasm (satellite cell origin) of the nurse cell [36].
• METHODS: BALB/c mice were intravenously injected with d-galactosamine (GalN, 20 mg/mouse)/tumor necrosis factor-alpha (TNF-alpha, 0.5 microg/mouse), or alphaFas (10 microg/mouse) 30 min after treatment with the caspase-9 inhibitor Ac-LEHD-CHO or pan-caspase inhibitor Z-VAD-fmk [37].

References