Combined experimental and computational analysis of DNA damage signaling reveals context‐dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress
Abstract 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 the...
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| Format: | Article |
| Language: | English |
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Springer Nature
2012-01-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb.2012.1 |
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| _version_ | 1849389451008016384 |
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| author | Andrea R Tentner Michael J Lee Gerry J Ostheimer Leona D Samson Douglas A Lauffenburger Michael B Yaffe |
| author_facet | Andrea R Tentner Michael J Lee Gerry J Ostheimer Leona D Samson Douglas A Lauffenburger Michael B Yaffe |
| author_sort | Andrea R Tentner |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-bfd0624a3a6749979c5ea2d602b7ad66 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-bfd0624a3a6749979c5ea2d602b7ad662025-08-20T03:41:57ZengSpringer NatureMolecular Systems Biology1744-42922012-01-018111810.1038/msb.2012.1Combined experimental and computational analysis of DNA damage signaling reveals context‐dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stressAndrea R Tentner0Michael J Lee1Gerry J Ostheimer2Leona D Samson3Douglas A Lauffenburger4Michael B Yaffe5Departments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyDepartments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyDepartments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyDepartments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyDepartments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyDepartments of Biology and Biological Engineering, David H Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyAbstract 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.https://doi.org/10.1038/msb.2012.1apoptosiscell‐cycle checkpointDNA damageErksignal transduction |
| spellingShingle | Andrea R Tentner Michael J Lee Gerry J Ostheimer Leona D Samson Douglas A Lauffenburger Michael B Yaffe Combined experimental and computational analysis of DNA damage signaling reveals context‐dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress Molecular Systems Biology apoptosis cell‐cycle checkpoint DNA damage Erk signal transduction |
| 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 | apoptosis cell‐cycle checkpoint DNA damage Erk signal transduction |
| url | https://doi.org/10.1038/msb.2012.1 |
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