Abstract
We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Carcinoma, Non-Small-Cell Lung / enzymology*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Proliferation
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Cellular Senescence
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Fibroblasts / enzymology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Genes, ras*
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Humans
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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MAP Kinase Kinase 1 / deficiency
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 2 / deficiency
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MAP Kinase Kinase 2 / genetics
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / deficiency
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 3 / deficiency
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Mitogen-Activated Protein Kinase 3 / genetics
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Proto-Oncogene Proteins B-raf / deficiency
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism*
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Proto-Oncogene Proteins c-raf / deficiency
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism*
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RNA Interference
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Signal Transduction
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Time Factors
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Transfection
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Tumor Burden
Substances
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BRAF protein, human
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Braf protein, mouse
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Map2k1 protein, mouse
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Map2k2 protein, mouse