Abstract
Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-β-activated kinase 1 (TAK1), an upstream regulator of IκB kinase (IKK), which controls canonical NF-κB signaling, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS-mutant colorectal cancer cell growth and survival. Here, we show that mutant KRAS upregulates glycogen synthase kinase 3α (GSK-3α), leading to its interaction with TAK1 to stabilize the TAK1-TAB complex to promote IKK activity. In addition, GSK-3α is required for promoting critical noncanonical NF-κB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with the loss of expression of oncogenic genes such as c-myc and TERT. These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways.
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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Cell Growth Processes / physiology
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Cell Line, Tumor
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Down-Regulation
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Mice
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism*
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Phosphorylation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins p21(ras)
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Signal Transduction
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Transcription Factors
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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KRAS protein, human
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NF-kappa B
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Proto-Oncogene Proteins
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TAB1 protein, MAPKKK activator, vertebrate
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Transcription Factors
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Glycogen Synthase Kinase 3
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glycogen synthase kinase 3 alpha
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Proto-Oncogene Proteins p21(ras)
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ras Proteins