1. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression
- Author
-
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, and Koumenis, Constantinos
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Cancer ,Activating Transcription Factor 4 ,Adaptor Proteins ,Signal Transducing ,Animals ,Cell Cycle Proteins ,Endoplasmic Reticulum Stress ,Genes ,myc ,Humans ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Transgenic ,Phosphoproteins ,Phosphorylation ,Protein Biosynthesis ,TOR Serine-Threonine Kinases ,Transcriptional Activation ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - 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.
- Published
- 2019