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Issue 4, 2010
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Integration of multiple signaling pathway activities resolves K-RAS/N-RAS mutation paradox in colon epithelial cell response to inflammatory cytokine stimulation

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Abstract

Colon tumors frequently harbor mutation in K-RAS and/or N-RAS, members of a GTPase family operating as a central hub for multiple key signaling pathways. While these proteins are strongly homologous, they exhibit diverse downstream effects on cell behavior. Utilizing an isogenic panel of human colon carcinoma cells bearing oncogenic mutations in K-RAS and/or N-RAS, we observed that K-RAS and double mutants similarly yield elevated apoptosis in response to treatment with TNFα compared to N-RAS mutants. Regardless, and in surprising contrast, key phospho-protein signals were more similar between N-RAS and dual mutants. This apparent contradiction could not be explained by any of the key signals individually, but a multi-pathway model constructed from the single-mutant cell line data was able to predict the behavior of the dual-mutant cell line. This success arises from a quantitative integration of multiple pro-apoptotic (pIκBα, pERK2) and pro-survival (pJNK, pHSP27) signals in manner not easily discerned from intuitive inspection.

Graphical abstract: Integration of multiple signaling pathway activities resolves K-RAS/N-RAS mutation paradox in colon epithelial cell response to inflammatory cytokine stimulation

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Publication details

The article was received on 09 Dec 2009, accepted on 01 Feb 2010 and first published on 08 Mar 2010


Article type: Paper
DOI: 10.1039/B925935J
Citation: Integr. Biol., 2010,2, 202-208
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    Integration of multiple signaling pathway activities resolves K-RAS/N-RAS mutation paradox in colon epithelial cell response to inflammatory cytokine stimulation

    P. K. Kreeger, Y. Wang, K. M. Haigis and D. A. Lauffenburger, Integr. Biol., 2010, 2, 202
    DOI: 10.1039/B925935J

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