Abstract
N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of inflammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP-ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics*
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Cell Line, Tumor
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Colitis / chemically induced
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Colitis / genetics*
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Colitis / pathology*
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Colorectal Neoplasms / prevention & control
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Disease Progression
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Extracellular Signal-Regulated MAP Kinases / metabolism
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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Genes, ras
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Humans
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MAP Kinase Signaling System / drug effects
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Proto-Oncogene Proteins c-raf / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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ras Proteins / genetics*
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ras Proteins / metabolism
Substances
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Membrane Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Proto-Oncogene Proteins c-raf
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Extracellular Signal-Regulated MAP Kinases
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GTP Phosphohydrolases
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NRAS protein, human
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ras Proteins