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

TitleCombined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress.
Publication TypeJournal Article
Year of Publication2012
AuthorsTentner, AR, Lee, MJ, Ostheimer, GJ, Samson, LD, Lauffenburger, DA, Yaffe, MB
JournalMol Syst Biol
Volume8
Pagination568
Date Published2012
ISSN1744-4292
KeywordsApoptosis, Cellular Microenvironment, Computational Biology, DNA Damage, Extracellular Signal-Regulated MAP Kinases, G1 Phase Cell Cycle Checkpoints, Humans, Models, Biological, Models, Theoretical, Signal Transduction, Stress, Physiological, Systems Biology, Tumor Cells, Cultured, Validation Studies as Topic
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 TNF╬▒ 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.

DOI10.1038/msb.2012.1
Alternate JournalMol. Syst. Biol.
PubMed ID22294094
PubMed Central IDPMC3296916
Grant ListCA112967 / CA / NCI NIH HHS / United States
ES015339 / ES / NIEHS NIH HHS / United States
GM60594 / GM / NIGMS NIH HHS / United States