ATF4 Couples MYC-dependent Translational Activity to Bioenergetic Demands During Tumour Progression

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Endoplasmic Reticulum Stress / genetics
  • Genes, myc / genetics*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Transgenic
  • Phosphoproteins / genetics
  • Phosphorylation
  • Protein Biosynthesis / physiology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptional Activation / physiology*

Substances

  • ATF4 protein, human
  • Adaptor Proteins, Signal Transducing
  • Atf4 protein, mouse
  • EIF4EBP1 protein, human
  • Phosphoproteins
  • Activating Transcription Factor 4
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1