ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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.
Subject(s)
Activating Transcription Factor 4/genetics , Genes, myc/genetics , Transcriptional Activation/physiology , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Cycle Proteins , Endoplasmic Reticulum Stress/genetics , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice, Transgenic , Phosphoproteins/genetics , Phosphorylation , Protein Biosynthesis/physiology , TOR Serine-Threonine Kinases/metabolismABSTRACT
To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase(-/-) mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase(-/-) mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvß3 integrin was reduced in caspase(-/-) tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvß3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.
