The mTOR pathway negatively controls ATM by up-regulating miRNAs.
basic_science · Level V
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- Record sourced from PubMed, PMID 23818585.
- Also identified by DOI 10.1073/pnas.1220898110 and PMC identifier 3718104.
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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.
Medical subject headings
- Cell Cycle Proteins
- DNA-Binding Proteins
- Gene Expression Regulation, Neoplastic
- Protein Serine-Threonine Kinases
- Sarcoma
- Signal Transduction
- TOR Serine-Threonine Kinases
- Tumor Suppressor Proteins