Abstract
The MYC protooncogene is frequently deregulated in human cancers. Here, by screening a kinase-directed library of small inhibitory RNAs, we identify glycogen synthase kinase 3beta (GSK3beta) as a gene whose inactivation potentiates TNF-related apoptosis-inducing ligand death receptor-mediated apoptosis specifically in MYC-overexpressing cells. Small inhibitory RNA-induced silencing of GSK3beta prevents phosphorylation of MYC on T58, thereby inhibiting recognition of MYC by the E3 ubiquitin ligase component FBW7. Attenuating the GSK3beta-FBW7 axis results in stabilization of MYC, up-regulation of surface levels of the TNF-related apoptosis-inducing ligand death receptor 5, and potentiation of death receptor 5-induced apoptosis in vitro and in vivo. These results identify GSK3beta and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3beta survival-signaling pathway. The results also demonstrate paradoxically that MYC-expressing tumors might be treatable by drug combinations that increase rather than decrease MYC oncoprotein function.
MeSH terms
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Caspase 8
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Caspases / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Survival
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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F-Box-WD Repeat-Containing Protein 7
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Gene Library
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Gene Silencing
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Cell Cycle Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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Membrane Glycoproteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10B protein, human
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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Ubiquitin-Protein Ligases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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CASP8 protein, human
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Caspase 8
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Caspases