Caspase activation - stepping on the gas or releasing the brakes? Lessons from humans and flies.
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.
Salvesen
Guy S
GS
Program in Apoptosis and Cell Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92122, USA. gsalvesen@burnham.org
Abrams
John M
JM
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D009369:Neoplasms / Q000473:pathology*; D011506:Proteins / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein
D016207:Cytokines; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases