- Tameire, Feven;
- Verginadis, Ioannis I;
- Leli, Nektaria Maria;
- Polte, Christine;
- Conn, Crystal S;
- Ojha, Rani;
- Salas Salinas, Carlo;
- Chinga, Frank;
- Monroy, Alexandra M;
- Fu, Weixuan;
- Wang, Paul;
- Kossenkov, Andrew;
- Ye, Jiangbin;
- Amaravadi, Ravi K;
- Ignatova, Zoya;
- Fuchs, Serge Y;
- Diehl, J Alan;
- Ruggero, Davide;
- Koumenis, Constantinos
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.