Abstract
The ataxia telangiectasia mutated (ATM) checkpoint is the central surveillance system that maintains genome integrity. We found that in the context of childhood sarcoma, mammalian target of rapamycin (mTOR) signaling suppresses ATM by up-regulating miRNAs targeting ATM. Pharmacological inhibition or genetic down-regulation of the mTOR pathway resulted in increase of ATM mRNA and protein both in mouse sarcoma xenografts and cultured cells. mTOR Complex 1 (mTORC1) suppresses ATM via S6K1/2 signaling pathways. microRNA-18a and microRNA-421, both of which target ATM, are positively controlled by mTOR signaling. Our findings have identified a negative feedback loop for the signaling between ATM and mTOR pathways and suggest that oncogenic growth signals may promote tumorigenesis by dampening the ATM checkpoint.
Keywords:
childhood cancer; kinase inhibitor.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Feedback, Physiological / physiology
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Female
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Gene Expression Regulation, Neoplastic / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Mice
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MicroRNAs / metabolism
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Morpholines
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Protein Serine-Threonine Kinases / metabolism*
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Sarcoma / metabolism*
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Signal Transduction / physiology*
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TOR Serine-Threonine Kinases / metabolism*
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Tumor Suppressor Proteins / metabolism*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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MIRN18A microRNA, human
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MIRN421 microRNA, human
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MicroRNAs
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Morpholines
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Tumor Suppressor Proteins
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(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
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mTOR protein, mouse
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases