Systems Biology of Death Receptor-Induced Apoptosis
Programmed cell death, termed apoptosis, plays a fundamental role in the development and homeostasis of multicellular organisms. Dysregulation of apoptosis can lead to numerous diseases, including autoimmune diseases, neurodegenerative diseases, and cancer. In mammalian cells apoptosis can be induced by intra- or extracellular stimuli. Extracellular stimuli comprise death ligands which lead to death receptor-induced apoptosis, referred to as extrinsic pathway. Intracellular signals, such as DNA damage, trigger the intrinsic pathway which results in the activation of Bcl-2 proteins and release of proapoptotic factors from the mitochondria into the cytosol. Apoptosis is executed by a family of cysteine proteases, the caspases, which eventually lead to the apoptotic phenotype, such as chromatin condensation, nuclear fragmentation, membrane blebbing, cell shrinkage, and formation of apoptotic bodies. The focus of this chapter is on understanding the signaling complexity of the extrinsic apoptotic pathway using systems biology. We summarize the main signaling paradigms and the major models of the extrinsic pathway. The development of these models has elucidated new insights into the regulation of apoptosis.
KeywordsInitiator Caspases Mitochondrial Outer Membrane Permeabilization Extrinsic Apoptosis Death Effector Domain CD95 Stimulation
We acknowledge the Helmholtz Alliance on Systems Biology (NW1SBCancer) and Helmholtz-Russia Joint Research Groups-2008-2 for supporting our work.
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