학술논문
ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression
Document Type
article
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; Koumenis, Constantinos
Source
Nature Cell Biology. 21(7)
Subject
Language
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.