Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein. Embo J ; 25 : — Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability. PLoS Comput Biol ; 2 : e Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis.
Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol Cell ; 30 : 11— Nakabayashi J , Sasaki A.
Understanding apoptosis by systems biology approaches.
J Theor Biol ; : — Mathematical modeling of the formation of apoptosome in intrinsic pathway of apoptosis. Systems and synthetic biology ; 2 : 49— Rsk-mediated phosphorylation and varepsilon binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J ; 31 : — MAP kinase signalling pathways in cancer. Oncogene ; 26 : — Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
Cancer Res ; 67 : — Oncogenesis ; 1 : e Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules. Human replication protein Cdc6 is selectively cleaved by caspase 3 during apoptosis. EMBO reports ; 3 : — EMBO J ; 28 : — Regulation of caspase-9 activity by differential binding to the apoptosome complex. Front Biosci ; 12 : — Diffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death.
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BMC Systems Biol ; 4 : 9. Local caspase activity directs engulfment of dendrites during pruning. Nat Neurosci ; 9 : — Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci ; 14 : 69— Hanahan D , Weinberg RA.
Hallmarks of cancer: the next generation. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy. Gut ; 61 : — Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.
Cell Death Disease ; 4 : e Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells. Poste G. Bring on the biomarkers. Turning tumors into vaccines: co-opting the innate immune system. Immunity ; 39 : 27— Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity ; 38 : — Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med ; 17 : — Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration.
Sci Signal ; 3 : ra A restricted cell population propagates glioblastoma growth after chemotherapy. Defining the mode of tumour growth by clonal analysis. Modeling evolutionary dynamics of epigenetic mutations in hierarchically organized tumors. PLoS Computational Biol ; 7 : e A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms. PloS One ; 8 : e A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks.
Front Physiol ; 2 : 4. Efficacy of weekly docetaxel and bevacizumab in mesenchymal chondrosarcoma: a new theranostic method combining xenografted biopsies with a mathematical model. Cancer Res ; 68 : — Reconsidering the paradigm of cancer immunotherapy by computationally aided real-time personalization. Cancer Res ; 72 : — Arrowsmith J. Trial watch: phase II failures: Nat Rev Drug Discov ; 10 : — Trial watch: phase III and submission failures: Nat Rev Drug Discov ; 10 : Nat Rev Drug Discov ; 9 : — Collecting and organizing systematic sets of protein data.
Mathematical modeling reveals threshold mechanism in CDinduced apoptosis.
Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol Cell ; 47 : — Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. Download references. Correspondence to M Rehm. To obtain permission to re-use content from this article visit RightsLink. Scientific Reports Article metrics. Advanced search. Skip to main content. Subjects Apoptosis Cancer therapeutic resistance Computational models Systems biology.
Abstract Our understanding of the mitochondrial or intrinsic apoptosis pathway and its role in chemotherapy resistance has increased significantly in recent years by a combination of experimental studies and mathematical modelling. Facts Mathematical modelling has provided mechanistic insight into cell death decisions during intrinsic apoptosis signalling by identifying network-level control functions that emanate from multi-protein interplay.
Open Questions Can systems models that accurately predict the responsiveness of cell lines to targeted apoptosis inducers and sensitisers be validated clinically? Figure 1 Convergence of complex apoptosis signals into a cell death decision — a simplified overview.
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Full size image. The Initiation of the Intrinsic Apoptosis Pathway — A Black Box for Kinetic Systems Modelling The initiation of the intrinsic pathway currently remains largely uncharted territory for kinetic systems modelling. Open Questions and Considerations Although experimentally validated models of apoptosis execution have been remarkably accurate for the investigated cell line systems, they are of limited detail concerning the early molecular processes following MOMP.
Translational Application of Systems Models of the Intrinsic Apoptosis Pathway Although defects in apoptosis signalling are a hallmark of cancer, 61 associating the expression of individual apoptosis proteins with cancer therapy resistance so far largely failed. Perspectives for the Integration of Apoptosis Pathway Models into Higher-Level and Multi-Scale Modelling Frameworks A major challenge for the further development and application of apoptosis pathway models is their integration into higher-level contexts that reflect organisational structures, processes and interactions that go beyond the single-cell level Figure 4.
Figure 4 Systems modelling in the context of biological scale and complexity. Future Challenges and Requirements for Apoptosis Systems Biology and Systems Medicine A general challenge both for basic and translational systems biological research of cell death processes is the lack of quantitative data, 82 in particular at the level of protein expression, protein activities, interactions and turnover rates.
References 1. Google Scholar 3. PubMed Article Google Scholar 4. Article Google Scholar PubMed Article Google Scholar About this article Publication history Received 26 October Revised 20 December Accepted 02 January Published 29 May Viruses spread from cell to cell through trigger waves, so it makes sense that our initial line of immune defense might employ the same tactic.
These ingredients are present all over the place in biological regulation. Now we want to know where else trigger waves are found. Materials provided by Stanford Medicine. Original written by Hanae Armitage. Note: Content may be edited for style and length. Science News. Inside a cell, death often occurs like the wave at a baseball game. Spreads like wildfire Trigger waves require two main elements: a positive feedback loop and a threshold think -- falling dominoes. The question was, did apoptosis also spread like that in cells as they naturally occur?
A wave of trigger waves So far, apoptosis is the only form of cell death in which trigger waves have been identified, but Ferrell is investigating other processes in biology to see if the continual waves might play a role. Story Source: Materials provided by Stanford Medicine. Apoptosis propagates through the cytoplasm as trigger waves. Science , DOI: ScienceDaily, 9 August Stanford Medicine. In apoptosis, cell death spreads through perpetuating waves. Retrieved June 21, from www.
Solving the Puzzle of Necroptosis Nov. However the time of commitment to irreversible activation of apoptosis varies between individual cells and depends on the antagonism between autophagy and apoptosis Figure 8. We suppose that extra crosstalk between crosstalk element and apoptosis inducer is essential for irreversibility, but identification of this regulatory loop needs experimental studies in the future. Moreover, the finding that the activation of the prosurvival factor autophagy seems to be an inevitable consequence of any kind of ER stresses suggests a therapeutic value for preconditioning with ER stress in a variety of human diseases.
The authors declare that there is no conflict of interests regarding the publication of this paper. The authors are thankful to Vinod P. University of Oxford, UK for critical reading of the paper and his helpful comments. BioMed Research International. Indexed in Science Citation Index Expanded. Journal Menu. Special Issues Menu. Subscribe to Table of Contents Alerts. Table of Contents Alerts. Abstract One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress.
Introduction The maintenance of intrinsic homeostasis in a multicellular organism is mainly dependent on the ability of cells to take precise actions with respect to external and internal stimuli such as nutrient availability, inflammatory mediators, and growth factors [ 1 , 2 ]. Materials and Methods 2.
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Statistics For densitometry analysis western blot data were acquired using ImageQuant 5. Mathematical Modeling The regulatory network was translated into a set of nonlinear ordinary differential equations ODEs and analyzed using the techniques of dynamical system theory [ 38 — 40 ]. Results 3. Figure 1: The schematic model of autophagy-apoptosis crosstalk during ER stress. The autophagy inducer, the apoptosis inducer, and the ER stress sensor ERSS are denoted by isolated green, red, and blue boxes, respectively. Dashed line shows how the molecules can influence each other, while blocked end lines denote inhibition.
Figure 2: The time course profile of cell treatment with respect to low and high levels of TM. Figure 3: The time course profile of cell treatment with respect to low and high levels of DTT. Figure 4: Stochastic simulation of cell population with respect to ER stress. Figure 5: The role of autophagy to determine the activation threshold for apoptosis.
The percentage of apoptotic cells was followed by Annexin dye errors bars represent standard deviation; asterisks indicate statistically significant difference from the control: ; d , e , and f. Figure 7: The irreversibility of apoptotic induction is tested by transient treatment with high level of ER stressor. Figure 8: Analyzing the effect of transient treatment with mathematical method.
Understanding apoptosis by systems biology approaches.
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