Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Constantinos Koumenis

Abstract

The ability of cancer cells to adapt to non-cell autonomous (extrinsic) and cell autonomous (intrinsic) stresses is critical for maintaining cell viability and therapy resistance. The Integrated Stress Response (ISR) transcription factor ATF4 is essential in helping cancer cells cope with extrinsic stresses such as deficits in oxygen and nutrients. ATF4 deficient cells exhibit decreased viability and survival when subjected to hypoxia or nutrient deprivation stresses. However the role of ATF4 in oncogene-induced intrinsic stress remains unclear. 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. This work shows that MYC induces ATF4 expression through activation of the ISR kinases PERK and GCN2. Using a tRNA microarray we discovered that MYC activates GCN2 through accumulation of uncharged tRNAs. Functionally, loss of ATF4 enhanced apoptosis and decreased survival during MYC activation. Genome-wide ChIP-seq analysis revealed that 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 mTORC1 target 4E-BP1 and genetic or pharmacological inhibition of mTORC1 signaling rescues ATF4 deficient cells from MYC-induced stress. To test the role of ATF4 in MYC induced tumorigenesis we employed the Eμ-Myc mouse model of MYC-induced spontaneous lymphoma. Acute deletion of ATF4 significantly delays MYC-driven tumor progression and increases survival in lymphoma and colon cancer xenograft models. Collectively, our results demonstrate ATF4 exerts pro-survival activities during MYC induced intrinsic stress and identifies ATF4 as a potential therapeutic target in MYC driven cancers.

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