Diffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death.

Hdl Handle:
http://hdl.handle.net/10147/93868
Title:
Diffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death.
Authors:
Huber, Heinrich J; Laussmann, Maike A; Prehn, Jochen Hm; Rehm, Markus
Affiliation:
Sytems Biology Group, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. heinhuber@rcsi.ie.
Citation:
Diffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death. 2010, 4 (1):9 BMC Syst Biol
Journal:
BMC systems biology
Issue Date:
2010
URI:
http://hdl.handle.net/10147/93868
DOI:
10.1186/1752-0509-4-9
PubMed ID:
20132548
Abstract:
ABSTRACT: BACKGROUND: Apoptosis is an essential cell death process throughout the entire life span of all metazoans and its deregulation in humans has been implicated in many proliferative and degenerative diseases. Mitochondrial outer membrane permeabilisation (MOMP) and activation of effector caspases are key processes during apoptosis signalling. MOMP can be subject to spatial coordination in human cancer cells, resulting in intracellular waves of cytochrome-c release. To investigate the consequences of these spatial anisotropies in mitochondrial permeabilisation on subsequent effector caspase activation, we devised a mathematical reaction-diffusion model building on a set of partial differential equations. RESULTS: Reaction-diffusion modelling suggested that even if strong spatial anisotropies existed during mitochondrial cytochrome c release, these would be eliminated by free diffusion of the cytosolic proteins that instantiate the apoptosis execution network. Experimentally, rapid sampling of mitochondrial permeabilisation and effector caspase activity in individual HeLa cervical cancer cells confirmed predictions of the reaction-diffusion model and demonstrated that the signalling network of apoptosis execution could efficiently translate spatial anisotropies in mitochondrial permeabilisation into a homogeneous effector caspase response throughout the cytosol. Further systems modelling suggested that a more than 10,000-fold impaired diffusivity would be required to maintain spatial anisotropies as observed during mitochondrial permeabilisation until the time effector caspases become activated. CONCLUSIONS: Multi-protein diffusion efficiently contributes to eliminating spatial asynchronies which are present during the initiation of apoptosis execution and thereby ensures homogeneous apoptosis execution throughout the entire cell body. For previously reported biological scenarios in which effector caspase activity was shown to be targeted selectively to specific subcellular regions additional mechanisms must exist that limit or spatially coordinate caspase activation and/or protect diffusing soluble caspase substrates from unwanted proteolysis.
Language:
en
ISSN:
1752-0509

Full metadata record

DC FieldValue Language
dc.contributor.authorHuber, Heinrich Jen
dc.contributor.authorLaussmann, Maike Aen
dc.contributor.authorPrehn, Jochen Hmen
dc.contributor.authorRehm, Markusen
dc.date.accessioned2010-03-08T14:45:43Z-
dc.date.available2010-03-08T14:45:43Z-
dc.date.issued2010-
dc.identifier.citationDiffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death. 2010, 4 (1):9 BMC Syst Biolen
dc.identifier.issn1752-0509-
dc.identifier.pmid20132548-
dc.identifier.doi10.1186/1752-0509-4-9-
dc.identifier.urihttp://hdl.handle.net/10147/93868-
dc.description.abstractABSTRACT: BACKGROUND: Apoptosis is an essential cell death process throughout the entire life span of all metazoans and its deregulation in humans has been implicated in many proliferative and degenerative diseases. Mitochondrial outer membrane permeabilisation (MOMP) and activation of effector caspases are key processes during apoptosis signalling. MOMP can be subject to spatial coordination in human cancer cells, resulting in intracellular waves of cytochrome-c release. To investigate the consequences of these spatial anisotropies in mitochondrial permeabilisation on subsequent effector caspase activation, we devised a mathematical reaction-diffusion model building on a set of partial differential equations. RESULTS: Reaction-diffusion modelling suggested that even if strong spatial anisotropies existed during mitochondrial cytochrome c release, these would be eliminated by free diffusion of the cytosolic proteins that instantiate the apoptosis execution network. Experimentally, rapid sampling of mitochondrial permeabilisation and effector caspase activity in individual HeLa cervical cancer cells confirmed predictions of the reaction-diffusion model and demonstrated that the signalling network of apoptosis execution could efficiently translate spatial anisotropies in mitochondrial permeabilisation into a homogeneous effector caspase response throughout the cytosol. Further systems modelling suggested that a more than 10,000-fold impaired diffusivity would be required to maintain spatial anisotropies as observed during mitochondrial permeabilisation until the time effector caspases become activated. CONCLUSIONS: Multi-protein diffusion efficiently contributes to eliminating spatial asynchronies which are present during the initiation of apoptosis execution and thereby ensures homogeneous apoptosis execution throughout the entire cell body. For previously reported biological scenarios in which effector caspase activity was shown to be targeted selectively to specific subcellular regions additional mechanisms must exist that limit or spatially coordinate caspase activation and/or protect diffusing soluble caspase substrates from unwanted proteolysis.-
dc.language.isoenen
dc.titleDiffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death.en
dc.contributor.departmentSytems Biology Group, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. heinhuber@rcsi.ie.en
dc.identifier.journalBMC systems biologyen
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