Caspase Activator

So far ten catalytically active caspases have been reported in mouse (caspase-1, -2, -3, -6, -7, -8, -9, -11, -12,-14) and eleven in human (caspase-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -14) (Fig. 1). Caspases are expressed as inactive proenzymes that contain an amino-terminal prodomain of variable length followed by two domains with conserved sequences a large subunit ( 20 kDa, p20) and a small carboxy-terminal subunit ( 10 kDa, plO). Caspases can be divided according to absence (-3, -6, -7, -14) or presence (-1, -2, -8, -9, -10, -11, -12) of an extended prodomain containing protein-protein interaction motifs belonging to the death domain (DD) superfamily, in particular the death effector domains (DED) and the caspase activation and recruitment domains (CARD). 

Caspases. Figure 2 Caspase activating complexes. Schematic representation of all described long prodomain caspase activation complexes. Each complex contains essentially three functionally different building blocks a sensor/platform, an adaptor and an effector in the form of a particular caspase. Some instigating ligands, possible outcomes and regulatory proteins are indicated. 

Caspases. Table 1 Diseases associated with inappropriate caspase activation. Contribution of apoptosis (A) and inflammation (I) are indicated... 

ALT, alanine aminotransferase ASC, apoptosis-associated speck-like protei containing a CARD AST, aspartate aminotransferase CARD, caspase activation and recruitment domains CD, Crohn s disease COP, CARD-only protein DD, death domain DED, death effector domains DIABLO, direct LAP-binding protein with low pi... 

Death domain (DD) superfamily consists of structurally related homotypic interaction motifs of approximately 90 amino acids. The motifs are organized in six antiparallel amphipathic a-helices, the so-called DD fold. The four members of the super family are the death domain (DD), the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the Pyrin domain. All are important mediators for the assembly of caspase activating complexes. 

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

Kruman 11, Nath A, Mattson MP (1998) HlV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154(2) 276-288... 

In some studies it has been shown that ITCs can cause increases in the pro-apoptotic caspase enzymes, caspase 3, caspase 8 or caspase However, in other work, specific caspase inhibitors failed to block cell death or cell detachment from the substratum . This suggests that caspase-activation may only be a bystander event, or may only occur after the initiating event of a block in the cell cycle. Indeed, although expression of c-Jun amino-terminal kinase (INK) in response to ITCs has been linked to the pro-apoptotic process, it remains entirely possible that this is a parallel signalling pathway, more closely related to the induction of Phase 1 or Phase 2 enzymes than to the... 

Rehm, M., Dussmann, H., Janicke, R. U., Tavare, J. M., Kogel, D. and Prehn, J. H. (2002). Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process. Role of caspase-3. J. Biol. Chem. 277, 24506-14. 

Gurtu, V., Kain, S. R. and Zhang, G. (1997). Fluorometric and colorimetric detection of caspase activity associated with apoptosis. Anal. Biochem. 251, 98-102. 

Several biological assays pointed to an unusual mechanism of action for 7, which is clearly different from cisplatin, as expected from its remarkable cytotoxic activity. For example, different levels of p53 and caspase activity were observed. Unusual... 

Classic antioxidants, vitamin E, vitamin C, and others can suppress the activation of apoptosis. For example, ascorbic acid prevented cytochrome c release and caspase activation in human leukemia cells exposed to hydrogen peroxide [128], Pretreatment with A -acctylcystcinc, ascorbate, and vitamin E decreased homocysteine thiolactone-induced apoptosis in human promyelocytic leukemia HL-60 cells [129]. Resveratrol protected rat brain mitochondria from anoxia-reoxygenation damage by the inhibition of cytochrome c release and the reduction of superoxide production [130]. However, it should be mentioned that the proapoptotic effect of ascorbate, gallic acid, or epigallocatechin gallate has been shown in the same human promyelocytic leukemia cells [131]. 

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Many of the morphological and biochemical changes that occur in cells that die by necrosis are very different from those that occur in apoptosis. During necrosis cells swell, mitochondria and endoplasmic reticulum lose their structure and become dysfunctional and the nuclear membrane becomes disrupted (Fig. 35-1). Necrotic death is independent of premitochondrial apoptotic proteins such as Bax, cytochrome c release and caspase activation. Necrosis is further distinguished from apoptosis by the fact that necrosis usually occurs as the result of a traumatic physical injury or stroke and cells die en masse, whereas apoptosis typically occurs in individual cells within a population of surviving neighbors. 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Miura, K., Aminova L., and MurayamaY. Fusarenon-X induced apoptosis in HL-60 cells depends on caspase activation and cytochrome c release. Toxicology 172, 103, 2002. 

Wolf, BB., Schuler, M., Echeverri, F. and Green. DR. (1999) J. Biol. Chem., Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation, 274, 30651-30556. 

Byrd, J., Kitada, S., Flinn, L, Aron, J., Pearson, M., Lucas, D., and Reed, J.C., The mechanism of tumor cell clearance by rituximab leukemia evidence of caspase activation and apoptosis induction. Blood, 99, 1038-1043, 2002. 

Du, C., et al., Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating lAP inhibition. Cell, 2000, 102(1), 33-42. 

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