Computational modeling of apoptotic signaling pathways induced by cisplatin

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Background: Apoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems. Results: Here, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose-and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level. Conclusions: Using this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis.
Publisher
BIOMED CENTRAL LTD
Issue Date
2012-09
Language
English
Article Type
Article
Keywords

ENDOPLASMIC-RETICULUM STRESS; MITOCHONDRIAL PERMEABILITY TRANSITION; TUBULAR EPITHELIAL-CELLS; INDUCED NEPHROTOXICITY; MOLECULAR-MECHANISMS; INDUCED INJURY; LLC-PK1 CELLS; CYTOCHROME-C; ACTIVATION; DEATH

Citation

BMC SYSTEMS BIOLOGY, v.6

ISSN
1752-0509
DOI
10.1186/1752-0509-6-122
URI
http://hdl.handle.net/10203/103681
Appears in Collection
BiS-Journal Papers(저널논문)
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