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ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
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ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
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ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
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Journal Article
ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
2012
Overview
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.
Publisher
Springer Netherlands,Springer Nature B.V
Subject
Activating Transcription Factor 4 - metabolism
/ Apoptosis Regulatory Proteins - genetics
/ Apoptosis Regulatory Proteins - metabolism
/ Biomedical and Life Sciences
/ Breast Neoplasms - pathology
/ Cancer
/ Female
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Hypoxia
/ Oligonucleotide Array Sequence Analysis
/ Promoter Regions, Genetic - genetics
/ Proteins
/ Proto-Oncogene Proteins - genetics
/ Proto-Oncogene Proteins - metabolism
/ Proto-Oncogene Proteins c-bcl-2 - genetics
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
