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.
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January 2013
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Research Article|
December 14 2012
Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival
Luke R. G. Pike
;
Luke R. G. Pike
*Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
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Dean C. Singleton
;
Dean C. Singleton
*Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
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Francesca Buffa
;
Francesca Buffa
*Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
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Olga Abramczyk
;
Olga Abramczyk
†Centre for Cancer Research and Cell Biology, Queen's University Belfast, CCRCB Building, Belfast, U.K.
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Kanchan Phadwal
;
Kanchan Phadwal
‡Nuffield Department of Medicine, NIHR, Biomedical Research Centre, John Radcliffe Hospital, Headington, Oxford, U.K.
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Ji-Liang Li
;
Ji-Liang Li
*Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
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Anna Katharina Simon
;
Anna Katharina Simon
‡Nuffield Department of Medicine, NIHR, Biomedical Research Centre, John Radcliffe Hospital, Headington, Oxford, U.K.
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James T. Murray
;
James T. Murray
§School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Romm 5.50, 152–160 Pearse Street, Trinity College Dublin, Dublin 2, Ireland
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Adrian L. Harris
Adrian L. Harris
1
*Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
1To whom correspondence should be addressed (email aharris.lab@imm.ox.ac.uk).
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Biochem J (2013) 449 (2): 389–400.
Article history
Received:
June 14 2012
Revision Received:
September 25 2012
Accepted:
October 18 2012
Accepted Manuscript online:
October 18 2012
Citation
Luke R. G. Pike, Dean C. Singleton, Francesca Buffa, Olga Abramczyk, Kanchan Phadwal, Ji-Liang Li, Anna Katharina Simon, James T. Murray, Adrian L. Harris; Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival. Biochem J 15 January 2013; 449 (2): 389–400. doi: https://doi.org/10.1042/BJ20120972
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