Activation of caspases

Active caspases 8, 9 and 10 can convert caspase-3, the most abundant effector caspase from its pro-form to its active cleaved form. Cleavage of a number of different substrates by caspase-3 and also by caspase-6 and -7 which are two other executioner caspases besides caspase-3 then results in the typical morphology which is characteristic of apoptosis. Yet, the activation of caspase-3 and also of caspase-9 can be counteracted by IAPs, so called inhibitor of apoptosis proteins. However, concomitantly with cytochrome C also other proteins are released from mitochondria, including Smac/DIABLO. Smac/DIABLO and potentially other factors can interact with IAPs and thereby neutralize their caspase-inhibitory activity. This releases the breaks on the cell death program and allows apoptosis to ensue. 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

Bacellar H, Munoz A et al (1994) Temporal trends in the incidence of HIV-l-related neurologic diseases Multicenter AIDS Cohort Study, 1985-1992. Neurology 44(10) 1892-1900 Banki K, Hutter E et al (1998) Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. . J Biol Chem 273(19) 11944-11953... 

Lee, J.I. et al., Beta-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases, Exp. Oncol., 28, 30, 2006. 

Topo inhibitors are found to be the most efficient inducers of apoptosis. The main pathways leading from topo-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by pro-apoptotic molecules released from mitochondria. In some cells, the apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic ef-... 

Cicala C, Arthos J, Rubbert A, et al. HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. Proc Natl Acad Sci U S A 2000 97(3) 1178-1183. 

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

Palozza, P., Serini, S., Torsello, A. et al. 2003a. Mechanism of activation of caspase cascade during beta-carotene-induced apoptosis in human tumor cells. Nutr Cancer 47 76-87. 

Takemoto, K., Nagai, T., Miyawaki, A. and Miura, M. (2003). Spatio-temporal activation of caspase revealed by indicator that is insensitive to environmental effects. J. Cell Biol. 160, 235—43. 

The postmitochondrial events of apoptosis include activation of the caspases. Cytochrome c binds to the protein Apaf-1 in the cytosol, resulting in the recruitment and activation of caspase-9, which in turn activates cas-pase-3 (Figs 35-4, 35-5). Fourteen different mammalian caspases have been identified and each may play a key role... 

Kang, S. J., Sanchez, I., Jing, N. and Yuan, J. Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis. /. Neurosci. 23 5455-5460, 2003. 

Granville DJ, Carthy CM, Jiang H, Shore GC, McManus BM, Hunt DW (1998) Rapid cytochrome c release, activation of caspases 3, 6, 7 and 8 followed by Bap31 cleavage in HeLa cells treated with photodynamic therapy. FEBS Lett 437 5-10. 

It is now well estahlished that activation of the caspase cascade is an indispensable and sufficient process in the execution phase of apoptosis (Nunez et al, 1998). As for mitochondria-mediated apoptosis, cytochrome c released from the mitochondrial inner membrane is well known to play an important role in the activation of caspase 9, one of the upstream proteases in the cascade (Zou et al, 1997). For activation of caspase 9, cytochrome c or apoptotic protease activating factor 2 (Apaf 2) induces the formation of the complex between Apaf 1 and caspase 9. The resultant activated caspase 9 then activates caspase 3, which in turn leads to the genomic DNA fragmentation and apoptotic cell death. 

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