ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia

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Item Type:	Article
Title:	ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
Creators Name:	Pike, L.R.G., Phadwal, K., Simon, A.K. and Harris, A.L
Abstract:	Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.
Keywords:	ATF4, Unfolded Protein Response, BH3-Only, Protein, Harakiri, HRK, Hypoxia, Integrated Stress, Response
Source:	Molecular Biology Reports
ISSN:	0301-4851
Publisher:	Springer
Volume:	39
Number:	12
Page Range:	10811-22
Date:	December 2012
Official Publication:	https://doi.org/10.1007/s11033-012-1975-3
PubMed:	View item in PubMed

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