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

  • Author(s): 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
  • et al.
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.

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