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Hypoxia in the microenvironment of many solid tumours is an important determinant of malignant progression. The ISR (integrated stress response) protects cells from the ER (endoplasmic reticulum) stress caused by severe hypoxia. Likewise, autophagy is a mechanism by which cancer cells can evade hypoxic cell death. In the present paper we report that the autophagy-initiating kinase ULK1 (UNC51-like kinase 1) is a direct transcriptional target of ATF4 (activating transcription factor 4), which drives the expression of ULK1 mRNA and protein in severe hypoxia and ER stress. We demonstrate that ULK1 is required for autophagy in severe hypoxia and that ablation of ULK1 causes caspase-3/7-independent cell death. Furthermore, we report that ULK1 expression is associated with a poor prognosis in breast cancer. Collectively, the findings of the present study identify transcriptional up-regulation of ULK1 as a novel arm of the ISR, and suggest ULK1 as a potentially effective target for cancer therapy.

Original publication

DOI

10.1042/bj20120972

Type

Journal article

Journal

The Biochemical journal

Publication Date

01/2013

Volume

449

Pages

389 - 400

Addresses

Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.

Keywords

Cell Line, Tumor, HCT116 Cells, HT29 Cells, Animals, Humans, Mice, Neoplasms, Breast Neoplasms, Protein-Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Blotting, Western, Prognosis, Multivariate Analysis, Survival Analysis, Reverse Transcriptase Polymerase Chain Reaction, Cell Hypoxia, Cell Survival, Gene Expression Regulation, Neoplastic, RNA Interference, Up-Regulation, Autophagy, Female, Activating Transcription Factor 4, Transcriptional Activation, Endoplasmic Reticulum Stress, MCF-7 Cells, Autophagy-Related Protein-1 Homolog