Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival

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Item Type:	Article
Title:	Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival
Creators Name:	Pike, L.R.G., Singleton, D.C., Buffa, F., Abramczyk, O., Phadwal, K., Li, J.L., Simon, A.K., Murray, J.T. and Harris, A.L.
Abstract:	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.
Keywords:	Autophagy, Endoplasmic Reticulum Stress, Hypoxia, Integrated Stress Response, UNC51-like Kinase 1 (ULK1), Unfolded Protein Response (UPR), Animals, Mice
Source:	Biochemical Journal
ISSN:	0264-6021
Publisher:	Portland Press
Volume:	449
Number:	2
Page Range:	389-400
Date:	15 January 2013
Official Publication:	https://doi.org/10.1042/BJ20120972
PubMed:	View item in PubMed

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