Caspases: the proteases of the apoptotic pathway

Abstract

Apoptosis, a morphologically defined form of physiological cell death, is implemented by a death machinery whose executionary arm is a family of cysteine proteases called caspases. These death proteases are part of a proteolytic caspase cascade that is activated by diverse apoptotic stimuli from outside and inside of the cell. The cell death machinery is evolutionarily conserved and composed of caspases and their regulatory components that include activators and repressors. These key components of the death machinery are linked to signaling pathways that are activated by either ligation of death receptors expressed at the cell surface or intracellular death signals. Caspases are normally present in the cell as proenzymes that require limited proteolysis for activation of enzymatic activity. Recent studies suggest that the basic mechanism of caspase activation is conserved in evolution. Binding of initiator caspase precursors to activator molecules appears to promote procaspase oligomerization and autoactivation. Enzymatic activation of initiator caspases leads to proteolytic activation of downstream (effector) caspases and cleavage of a number of vital proteins, resulting in the orderly demise and removal of the cell.

Ablation of microvessels in vivo upon dimerization of iCaspase-9

“…24 As expected, treatment with AP20187 did not cause processing of endogenous caspase-3 in HDMECs transduced with control viruses (Figure 3a). In contrast, HDMEC-…”

“…These results are consistent with previous observations that showed that factors such as VEGF promote endothelial cell survival by acting on various molecules including Bcl-2 and Akt, [2][3][4] that are known to function upstream of caspase-9 in the apoptosis pathway. 24 Most anti-angiogenic strategies currently in clinical trials are based on the delivery of antibodies or drugs that inhibit endothelial cell-specific survival signals and promote apoptosis by a default mechanism. In these approaches, the therapeutic agents are inherently targeted to the endothelium, but most of these agents induce moderate levels of apoptosis.…”

A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells

“…It was also speci®c to this antibody as not reproduced with anti-p110b or anti-p110g antibody. Finally antip110a-induced cell death was reversed when pretreating cells with 0.1 mM z-VAD-fmk, a general inhibitor of proteases of the caspase family, known to mediate apoptotic signals (Nunez et al, 1998). From these data, we concluded that PI3Ka plays an important role in carcinoma cell survival.…”

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

“…caspase-8) and executor (e.g. caspase-3), based on their roles in the apoptotic signalling cascade (Salvesen and Dixit, 1997;Nunez et al, 1998). Depending on apoptotic signal and cell type, activation of initiator caspases may lead to mitochondria-dependent and/or -independent activation of executor caspases; whereas the former requires cytochrome c release and activation of caspase-9 as consequences of mitochondria damage, the latter is characterised by a cytochrome-c-and caspase-9-independent activation of executor caspases (Krammer, 2000).…”