1. ¹Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
2. ²Department of Pharmacy, Center of Drug Research, Pharmaceutical Biology-Biotechnology, Munich, Germany
3. ³Department of Hematology/Oncology, University of Leipzig, Germany
4. ⁴Center of Physiology and Pathophysiology, Department of Heart and Circulatory Physiology, Georg-August University of Gottingen, Gottingen, Germany
5. ⁵Institute of Physiology, Cellular Oxygen Physiology, University of Zurich, Zurich, Switzerland
6. ⁶Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
7. ⁷Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, the Ohio State University, Columbus, OH, USA
8. ⁸Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Cancer Research UK, Oxford, UK

Correspondence: Dr K Ameri, Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, CCSR-South, 269 Campus Dr, Stanford, CA 94305, USA. E-mail: kameri@stanford.edu

⁹These two authors contributed equally as senior authors

Received 19 August 2005; Revised 24 April 2006; Accepted 24 May 2006; Published online 17 July 2006.

Abstract

Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.