Molecular Biology Reports

, Volume 39, Issue 12, pp 10811–10822 | Cite as

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

  • Luke R. G. Pike
  • Kanchan Phadwal
  • Anna Katharina Simon
  • Adrian L. Harris


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.


ATF4 Unfolded protein response BH3-only protein Harakiri HRK Hypoxia Integrated stress response 



Funding from Cancer Research UK, the Rhodes Trust, and the Natural Sciences and Engineering Research Council of Canada supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors declare no competing interests, financial or otherwise.

Supplementary material

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Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Luke R. G. Pike
    • 1
  • Kanchan Phadwal
    • 2
    • 3
  • Anna Katharina Simon
    • 2
    • 3
  • Adrian L. Harris
    • 1
  1. 1.Growth Factor Group, Cancer Research UK, Molecular Oncology LaboratoriesWeatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of OxfordOxfordUK
  2. 2.Nuffield Department of MedicineWeatherall Institute of Molecular Medicine, John Radcliffe HospitalOxfordUK
  3. 3.BRC Translational Immunology BRC lab, NIHROxfordUK

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