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Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress

Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenot...

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Autores principales: Tentner, Andrea R, Lee, Michael J, Ostheimer, Gerry J, Samson, Leona D, Lauffenburger, Douglas A, Yaffe, Michael B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Molecular Biology Organization 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296916/
https://www.ncbi.nlm.nih.gov/pubmed/22294094
http://dx.doi.org/10.1038/msb.2012.1
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author Tentner, Andrea R
Lee, Michael J
Ostheimer, Gerry J
Samson, Leona D
Lauffenburger, Douglas A
Yaffe, Michael B
author_facet Tentner, Andrea R
Lee, Michael J
Ostheimer, Gerry J
Samson, Leona D
Lauffenburger, Douglas A
Yaffe, Michael B
author_sort Tentner, Andrea R
collection PubMed
description Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time-resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin-induced DNA damage in the presence or absence of TNFα co-treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell-cycle regulatory responses. Two relational modeling approaches were then used to identify network-level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term ‘time-interval stepwise regression.’ Taken together, the results from these analysis methods revealed complex, cytokine-modulated inter-relationships among multiple signaling pathways following DNA damage, and identified an unexpected context-dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug.
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spelling pubmed-32969162012-03-08 Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress Tentner, Andrea R Lee, Michael J Ostheimer, Gerry J Samson, Leona D Lauffenburger, Douglas A Yaffe, Michael B Mol Syst Biol Article Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time-resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin-induced DNA damage in the presence or absence of TNFα co-treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell-cycle regulatory responses. Two relational modeling approaches were then used to identify network-level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term ‘time-interval stepwise regression.’ Taken together, the results from these analysis methods revealed complex, cytokine-modulated inter-relationships among multiple signaling pathways following DNA damage, and identified an unexpected context-dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug. European Molecular Biology Organization 2012-01-31 /pmc/articles/PMC3296916/ /pubmed/22294094 http://dx.doi.org/10.1038/msb.2012.1 Text en Copyright © 2012, EMBO and Macmillan Publishers Limited https://creativecommons.org/licenses/by-nc-sa/3.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial Share Alike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.
spellingShingle Article
Tentner, Andrea R
Lee, Michael J
Ostheimer, Gerry J
Samson, Leona D
Lauffenburger, Douglas A
Yaffe, Michael B
Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title_full Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title_fullStr Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title_full_unstemmed Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title_short Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
title_sort combined experimental and computational analysis of dna damage signaling reveals context-dependent roles for erk in apoptosis and g1/s arrest after genotoxic stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296916/
https://www.ncbi.nlm.nih.gov/pubmed/22294094
http://dx.doi.org/10.1038/msb.2012.1
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