Caspase activation – stepping on the gas or releasing the brakes? Lessons from humans and flies

Abstract

The central components of the execution phase of apoptosis in worms, flies, and humans are members of the caspase protease family. Work in Drosophila and mammalian systems has revealed a web of interactions that govern the activity of these proteases, and two fundamental control points have been identified. These are zymogen activation -the process that converts a latent caspase into its active form, and inhibition of the resulting active protease. In humans, the driving force for caspase activity is activation of the zymogens, but in Drosophila, a major thrust is derepression of caspase inhibitors. In this review, we consider evidence for these two distinct events in terms of the regulation of caspase activity. This sets the scene for therapy to reinstate the normal death mechanisms that have been overcome in a cancer cell's quest for immortality.

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

“…During apoptosis, activation of caspases involves proteolytic processing, cleaving off an N-terminal prodomain, and generating the large and the small catalytic subunits (reviewed in Ref. 1 ).…”

“…Initiator caspases contain long prodomains that harbor regulatory motifs such as the caspase activation and recruitment domain (CARD) in the prodomain of Caspase-9. 1 These regulatory motifs serve as binding sites for upstream apoptotic signaling factors. For example, through homotypic interactions of the CARD motif of Caspase-9 with the CARD motif of Apaf-1, Caspase-9 is recruited into the apoptosome, a large multisubunit complex, where it undergoes autoprocessing and activation.…”

“…For example, through homotypic interactions of the CARD motif of Caspase-9 with the CARD motif of Apaf-1, Caspase-9 is recruited into the apoptosome, a large multisubunit complex, where it undergoes autoprocessing and activation. 1 Once activated, Caspase-9 cleaves and activates the effector Caspase-3, which is characterized by the presence of a short prodomain. Effector caspases execute the cell death process by cleaving a large number of cellular proteins, triggering the morphological events leading to apoptotic cell death.…”

“…3 The Drosophila genome contains a total of seven caspase genes, three of which encode putative initiator caspases (Drosophila Nedd-2 like Caspase (Dronc), Dredd and Strica), whereas the remaining four are putative effector caspases (Drosophila ICE (DrICE), death caspase-1 (Dcp-1), Decay and Damm) (reviewed in Ref. 1,6 ). Mutations in these caspase genes that would allow their genetic characterization have been described for dredd, dcp-1 and dronc.…”

Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder

“…The caspase family proteases are key proteins in apoptotic signaling pathways, [28][29][30] while the intrinsic inhibitor of apoptosis proteins (IAP) effectively prevent apoptosis by antagonizing the caspases or inhibiting other proapoptotic proteins, in addition to participating in cell cycle progression and control of cell division. 31,32 In addition, mitochondrial proteins APAF1 and SMAC are also key proapoptotic proteins released upon apoptotic stimuli, which are involved in caspase activation and inhibition of IAPs, respectively.…”