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Nat Cell Biol. 2019 Jul;21(7):889-899. doi: 10.1038/s41556-019-0347-9. Epub 2019 Jul 1.

ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

Author information

1
Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
3
School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
4
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Penn Bioinformatics Core, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.
6
Center for Chemical Biology and Translational Medicine, The Wistar Institute, Philadelphia, PA, USA.
7
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
8
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
10
Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. koumenis@upenn.edu.

Abstract

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression.

PMID:
31263264
PMCID:
PMC6608727
[Available on 2020-01-01]
DOI:
10.1038/s41556-019-0347-9
[Indexed for MEDLINE]

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