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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1876-1882. Prepublished online as a Blood First Edition Paper on November 6, 2003November 20, 2003; DOI 10.1182/blood-2003-06-1859. This Article Full Text (PDF) All Versions of this Article: 2003-06-1859v1 2003-06-1859v2 103/5/1876    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ameri, K. Articles by Harris, A. L Search for Related Content PubMed PubMed Citation Articles by Ameri, K. Articles by Harris, A. L Social Bookmarking                   What's this? Submitted June 16, 2003 Accepted October 24, 2003 Anoxic induction of ATF-4 via HIF-1 independent pathways of protein stabilization in human cancer cells Kurosh Ameri, Claire E Lewis, Martin Raida, Heidi Sowter, Tsonwin Hai, and Adrian L Harris* Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Cancer Research UK, Oxford, United Kingdom Section of Oncology, Sheffield Medical School, Division of Genomic Medicine, Sheffield Medical School, Sheffield, United Kingdom Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, The Ohio State University, Columbus, OH, USA * Corresponding author; email: aharris.lab{at}cancer.org.uk. Hypoxia is a key factor in tumor development, contributing to angiogenesis and radiotherapy resistance. HIF-1 is a major transcription factor regulating the response of cancer cells to hypoxia. However, tumors also contain areas of more severe oxygen depletion, anoxia. Mechanisms for survival under anoxia are HIF-1 independent in Caenorhabditis elegans and thus, differ from the hypoxic response. Here we report a differential response of cancer cells to hypoxia versus anoxia by demonstrating the induction of ATF-4 and GADD153 protein specifically in anoxia with lack of induction in hypoxia. By applying RNAi, ATF-4 induction in anoxia was shown to be independent of HIF-1, and desferrioxamine and cobalt chloride induced HIF-1 but not ATF-4 or GADD153. Furthermore, the inductive response of ATF-4 and GADD153 was not related to alterations or arrest of mitochondrial respiration and was also independent of VHL mutations. In reoxygenated anoxic cells, ATF-4 had a half life of less than 5 minutes, and addition of proteasome inhibitor to normoxic cells upregulated ATF-4 protein. Extracts from primary human tumors demonstrated greater ATF-4 expression in tumors near necrotic areas. 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