Date of Award

Spring 5-17-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Constantinos Koumenis

Abstract

The transcription factor ATF4 regulates the expression of mRNAs involved in amino acid metabolism, redox homeostasis and ER stress responses. Its overexpression in human solid tumors suggests an important role in tumor biology. Here we report that inhibition of ATF4 expression blocks proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS). Overexpression of ASNS or supplementation of asparagine in trans, reverses the proliferation block and increases survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumors, activate the upstream eIF2 alpha kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. Levels of total GCN2, phospho-GCN2 and phospho-eIF2 alpha were upregulated in samples of human and mouse tumors compared to normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo. ATF4 also contributes to the hypoxic resistance of tumor cells. We conclude that the GCN2-eIF2 alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumor cells, making it a novel and attractive target for anti-tumor therapy.

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