ArticleProceedings of the National Academy of Sciences of the United States of America2015
Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Dynamical analysis of a model of BCL-2-dependent cellular decision making.NPJ systems biology and applications · 2025Article
- Computational modelling of aggressive B-cell lymphoma.Biochemical Society transactions · 2025Review
- Engineering Cell Fate with Adaptive Feedback Control.ACS synthetic biology · 2025Article
- Repercussions of the Calpain Cleavage-Related Missense Mutations in the Cytosolic Domains of Human Integrin-β Subunits on the Calpain-Integrin Signaling Axis.International journal of molecular sciences · 2025Article
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
- Computational modeling of DLBCL predicts response to BH3-mimetics.NPJ systems biology and applications · 2023Article
- Molecular Dynamics Simulations Predict That rSNP Located in theBiomolecules · 2020Article
- The Oscillation Amplitude, Not the Frequency of Cytosolic Calcium, Regulates Apoptosis Induction.iScience · 2020Article
- Measuring the affinity of protein-protein interactions on a single-molecule level by mass photometry.Analytical biochemistry · 2020Article
- System-based approaches as prognostic tools for glioblastoma.BMC cancer · 2019Review
- MERIT: Systematic Analysis and Characterization of Mutational Effect on RNA Interactome Topology.Hepatology (Baltimore, Md.) · 2019Article
- Systems analysis of phosphorylation-regulated Bcl-2 interactions establishes a model to reconcile the controversy over the significance of Bcl-2 phosphorylation.British journal of pharmacology · 2019Article
- Mathematical modeling and computational prediction of cancer drug resistance.Briefings in bioinformatics · 2018Review
- Assigning function to natural allelic variation via dynamic modeling of gene network induction.Molecular systems biology · 2018Article
- Parameter sensitivity analysis for a stochastic model of mitochondrial apoptosis pathway.PloS one · 2018Article
- Article
- Interrogating the topological robustness of gene regulatory circuits by randomization.PLoS computational biology · 2017Article
- Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane.Scientific reports · 2016Article
- Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway.Science signaling · 2016Article
- Synonymous mutations in oncogenesis and apoptosis versus survival unveiled by network modeling.Oncotarget · 2016Article
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4 authors.
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No grant is acknowledged in the PubMed record.
Abstract
It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant-wild-type and 16 matched SNP--wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation.
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