Caspase cascade

Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D EmUia DM, Fiiedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci 22 4015-4024... 

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. 

NO may react with superoxide to yield the highly reactive peroxynitrite, ONOO-. Superoxide may also be converted into H202 and the reactive hydroxyl radical, OH. In this way excessive activation of glutamate receptors leads to oxidative damage. The calcium influx has a major effect on mitochondria and causes them to depolarize and swell. This leads to a pore being formed in the outer mitochondrial membrane, which allows the escape of cytochrome c and procaspases from the mitochondria into the cytosol. Cytochrome c activates the caspase cascade, which leads to apoptotic cell death (Ch. 35). 

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. 

Liu, W., Kato, M., Akhand, A.A., Hayakawa, A., Suzuki, H., MiyataT., Kurokawa, K., Hotta, Y., Ishikawa, N., and Nakashima, I., 2000, 4-hydroxynonenal induces a ceUular redox status-related activation of the caspase cascade forapoptotic cell death, J. Cell. Sci. 113 635-461. 

The cytosolic targets of cathepsin D have not been ascertained. However, since we found that inhibition of cathepsin D prevented both release of cytochrome c and activation of caspase-3-like caspases, we suggest that cathepsin D exerts its effect upstream of both the release of cytochrome c from mitochondria and the onset of the caspase cascade. Cathepsin B seems to be of minor importance in this system, because we observed that the activity of cathepsin B decreased and the cathepsin B inhibitor CA074-Me had no influence on the rate of apoptosis (Kagedal et al 2001). 

Caspase-8 activates the effector caspases either directly, or indirectly by promoting the cytochrome c (see p. 140) from mitochondria. Once in the cytoplasm, cytochrome c binds to and activates the protein Apaf-1 (not shown) and thus triggers the caspase cascade. Apoptotic signals can also come from the cell nucleus. If irreparable DNA damage is present, the p53 protein (see p. 394)—the product of a tumor suppressor gene—promotes apoptosis and thus helps eliminate the defective cell. 

Prelytic DNA fragmentation Release of various factor (e.g., cytochrome C) into cytoplasm by mitochondria Caspase cascade is activated Alterations in membrane asymmetry... 

Niwa, M., Kara, A., Kanamori, Y, Matsuno, H., Kozawa, O., Yoshimi, N., Mori, H., and Uematsu, T., Inhibition of tumor necrosis factor-ct induced neutrophil apoptosis by cyclic AMP Involvement of caspase cascade. Eur. J. Pharmacol. 371, 59-67 (1999). 

Tlie initiator caspases receive proapoptotic signals and initiate the activation of a caspase cascade. Tliey are activated by an interaction with a transmembrane receptor or by cytotoxic influences. A complex is thus formed known as the apoptosome (see 15.4). The effector caspases are activated by an upstream caspase via a cascade mechanism. They are the component that executes apoptosis, initiates degradation of central proteins and directs the cell to death. 

An essential part of the apoptotic program is a caspase cascade. Apoptosis is initiated by proteolytic processing of intiator-procapsases under the influence of a variety of signals. The mature initiator caspase catalyzes the processing of a effector-procaspase to the active enzyme, which degrades specific substrates and/or activates further procaspases. In this way, caspases can be activated sequentially in a protease cascade. 

Procaspase 8 functions as an initiator caspase in this system, since its activation is the signal for activation of the downstream caspase cascade. The DED motif of caspase 8 is localized in its large prodomain. Similar motives are foimd in other caspases with large prodomains (caspases 2, 8 and 9). 

Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ (1999), Ordering the cytochrome C-initiated caspase cascade hierarchical activation of caspases-2, -3, -6, -7, -8 and -10 in a caspase-9-dependent manner, J. Cell Biol. 144 281-292. 

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