| First Author | Tameire F | Year | 2019 |
| Journal | Nat Cell Biol | Volume | 21 |
| Issue | 7 | Pages | 889-899 |
| PubMed ID | 31263264 | Mgi Jnum | J:332535 |
| Mgi Id | MGI:6384185 | Doi | 10.1038/s41556-019-0347-9 |
| Citation | Tameire F, et al. (2019) ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat Cell Biol 21(7):889-899 |
| abstractText | 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. |
