The MTOR Pathway Negatively Controls ATM by Up-regulating MiRNAs

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Jul 3

PMID 23818585

Citations 29

Authors

Changxian Shen

Peter J Houghton

Affiliations

Soon will be listed here.

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.

Citing Articles

PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction and .

Frohlich L, Niessner H, Sauer B, Kamereit S, Chatziioannou E, Riel S Cancer Res Commun. 2023; 3(9):1743-1755.

PMID: 37674529 PMC: 10478790. DOI: 10.1158/2767-9764.CRC-23-0101.

Rapamycin improves the developmental competence of human oocytes by alleviating DNA damage during IVM.

Yang Q, Xi Q, Wang M, Liu J, Li Z, Hu J Hum Reprod Open. 2022; 2022(4):hoac050.

PMID: 36518986 PMC: 9731209. DOI: 10.1093/hropen/hoac050.

S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair.

Amar-Schwartz A, Ben Hur V, Jbara A, Cohen Y, Barnabas G, Arbib E Elife. 2022; 11.

PMID: 36189922 PMC: 9529248. DOI: 10.7554/eLife.79128.

The Coordination of mTOR Signaling and Non-Coding RNA in Regulating Epileptic Neuroinflammation.

Zeng C, Hu J, Chen F, Huang T, Zhang L Front Immunol. 2022; 13:924642.

PMID: 35898503 PMC: 9310657. DOI: 10.3389/fimmu.2022.924642.

Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness.

Pieren D, Smits N, Imholz S, Nagarajah B, van Oostrom C, Brandt R Front Aging. 2022; 2.

PMID: 35474946 PMC: 9037984. DOI: 10.3389/fragi.2021.667193.

References

Vogelstein B, Kinzler K . The multistep nature of cancer. Trends Genet. 1993; 9(4):138-41. DOI: 10.1016/0168-9525(93)90209-z. View

Vousden K, Lane D . p53 in health and disease. Nat Rev Mol Cell Biol. 2007; 8(4):275-83. DOI: 10.1038/nrm2147. View

Kastan M, Bartek J . Cell-cycle checkpoints and cancer. Nature. 2004; 432(7015):316-23. DOI: 10.1038/nature03097. View

Hu H, Du L, Nagabayashi G, Seeger R, Gatti R . ATM is down-regulated by N-Myc-regulated microRNA-421. Proc Natl Acad Sci U S A. 2010; 107(4):1506-11. PMC: 2824372. DOI: 10.1073/pnas.0907763107. View

Levine A, Feng Z, Mak T, You H, Jin S . Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 2006; 20(3):267-75. DOI: 10.1101/gad.1363206. View

Cam H, Easton J, High A, Houghton P . mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell. 2010; 40(4):509-20. PMC: 3004768. DOI: 10.1016/j.molcel.2010.10.030. View

Zoncu R, Efeyan A, Sabatini D . mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2010; 12(1):21-35. PMC: 3390257. DOI: 10.1038/nrm3025. View

Sarbassov D, Guertin D, Ali S, Sabatini D . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712):1098-101. DOI: 10.1126/science.1106148. View

Song L, Lin C, Wu Z, Gong H, Zeng Y, Wu J . miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase. PLoS One. 2011; 6(9):e25454. PMC: 3181320. DOI: 10.1371/journal.pone.0025454. View

10.

Toffolatti L, Frascella E, Ninfo V, Gambini C, Forni M, Carli M . MYCN expression in human rhabdomyosarcoma cell lines and tumour samples. J Pathol. 2002; 196(4):450-8. DOI: 10.1002/path.1068. View

11.

Johnsen J, Segerstrom L, Orrego A, Elfman L, Henriksson M, Kagedal B . Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene. 2007; 27(20):2910-22. DOI: 10.1038/sj.onc.1210938. View

12.

Terrile M, Bryan K, Vaughan L, Hallsworth A, Webber H, Chesler L . miRNA expression profiling of the murine TH-MYCN neuroblastoma model reveals similarities with human tumors and identifies novel candidate miRNAs. PLoS One. 2011; 6(12):e28356. PMC: 3229581. DOI: 10.1371/journal.pone.0028356. View

13.

Brugarolas J, Lei K, Hurley R, Manning B, Reiling J, Hafen E . Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004; 18(23):2893-904. PMC: 534650. DOI: 10.1101/gad.1256804. View

14.

Varmus H . The new era in cancer research. Science. 2006; 312(5777):1162-5. DOI: 10.1126/science.1126758. View

15.

Levine A, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009; 9(10):749-58. PMC: 2771725. DOI: 10.1038/nrc2723. View

16.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

17.

Salk J, Fox E, Loeb L . Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Pathol. 2009; 5:51-75. PMC: 3375045. DOI: 10.1146/annurev-pathol-121808-102113. View

18.

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

19.

Zhang P, Bhakta K, Puri P, Newbury R, Feramisco J, Wang J . Association of ataxia telangiectasia mutated (ATM) gene mutation/deletion with rhabdomyosarcoma. Cancer Biol Ther. 2003; 2(1):87-91. DOI: 10.4161/cbt.231. View

20.

Wei J, Johansson P, Chen Q, Song Y, Durinck S, Wen X . microRNA profiling identifies cancer-specific and prognostic signatures in pediatric malignancies. Clin Cancer Res. 2009; 15(17):5560-8. PMC: 2737097. DOI: 10.1158/1078-0432.CCR-08-3287. View