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

ABSTRACT: Dysregulation of the proto-oncogene c-Myc (MYC henceforward) drives malignant progression, but also induces robust anabolic and proliferative programs leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. We have uncovered an essential role for the transcription factor ATF4 in cell survival following MYC activation. MYC- upregulates ATF4 by activating GCN2 kinase through uncharged tRNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC target genes, including those regulating amino acid biosynthesis/transport and protein synthesis. ATF4 is essential for MYC-induced upregulation of the negative translational regulator and mTOR target 4E-BP1 and genetic or pharmacological inhibition of mTOR signaling rescues ATF4 deficient cells from MYC-induced stress. Acute deletion of ATF4 significantly delays MYC-driven tumor progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC-activity, ensuring enhanced translation rates are compatible with survival and tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117240 | GEO | 2018/07/18

REPOSITORIES: GEO

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

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