Mathematical modeling of the regulation of caspase-3 activation and degradation.
Caspases are thought to be important players in the execution process of apoptosis. Inhibitors of apoptosis (IAPs) are able to block caspases and therefore apoptosis. The fact that a subgroup of the IAP family inhibits active caspases implies that not each caspase activation necessarily leads to apoptosis. In such a scenario, however, processed and enzymically active caspases should somehow be removed. Indeed, IAP-caspase complexes covalently bind ubiquitin, resulting in degradation by the 26S proteasome. Following release from mitochondria, IAP antagonists (e.g. second mitochondrial activator of caspases (Smac)) inactivate IAPs. Moreover, although pro-apoptotic factors such as irradiation or anti-cancer drugs may release Smac from mitochondria in tumor cells, high cytoplasmic survivin and ML-IAP levels might be able to neutralize it and, consequently, IAPs would further be able to bind activated caspases. Here, we propose a simple mathematical model, describing the molecular interactions between Smac deactivators, Smac, IAPs, and caspase-3, including the requirements for both induction and prevention of apoptosis, respectively. In addition, we predict a novel mechanism of caspase-3 degradation that might be particularly relevant in long-living cells.
Stucki
Jörg W
JW
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. joerg.stucki@pki.unibe.ch
Simon
Hans-Uwe
HU
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D000077022:Survivin
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; C419866:BIRC7 protein, human; D002352:Carrier Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases