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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3610-3617. Prepublished online as a Blood First Edition Paper on August 7, 2007; DOI 10.1182/blood-2007-06-094441. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-06-094441v1 110/10/3610    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Köditz, J. Articles by Katschinski, D. M. Search for Related Content PubMed PubMed Citation Articles by Köditz, J. Articles by Katschinski, D. M. Related Collections Hematopoiesis and Stem Cells Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor Jens Köditz1, Jutta Nesper2, Marieke Wottawa1, Daniel P. Stiehl3, Gieri Camenisch3, Corinna Franke2, Johanna Myllyharju4, Roland H. Wenger3, and Dörthe M. Katschinski1 1 Department of Heart and Circulatory Physiology, Center of Physiology and Pathophysiology, Georg-August University Göttingen, Göttingen, Germany; 2 Cell Physiology Group, Medical Faculty, Martin-Luther University Halle, Halle, Germany; 3 Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; and 4 Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following endoplasmic reticulum (ER) stress, and is a critical regulator of cell fate. Here, we identified the zipper II domain of ATF-4 to interact with the oxygen sensor prolyl-4-hydroxylase domain 3 (PHD3). The PHD inhibitors dimethyloxalylglycine (DMOG) and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability, but was independent of the ubiquitin ligase von Hippel–Lindau protein (pVHL). A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of 5 prolyl residues within this ODD domain or siRNA-mediated down-regulation of PHD3, but not of PHD2, was sufficient to stabilize ATF-4 under normoxic conditions. These data demonstrate that PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems, and hence not only confers adaptive responses but also cell fate decisions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A wrinkle in the unfolding of hypoxic response: HIF and ATF4 Alexander Weidemann and Randall S. Johnson Blood 2007 110: 3492-3493. [Full Text] [PDF] This article has been cited by other articles: J. A. Garcia Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR Sci. Signal., November 10, 2009; 2(96): pe70 - pe70. [Abstract] [Full Text] [PDF] S. A. Gerber, B. Yatsula, C. L. Maier, T. J. Sadler, L. W. Whittaker, and J. S. Pober Interferon-Gamma Induces Prolyl Hydroxylase (PHD)3 Through a STAT1-Dependent Mechanism in Human Endothelial Cells Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1363 - 1369. [Abstract] [Full Text] [PDF] D. A. Tennant, R. V. Duran, H. Boulahbel, and E. Gottlieb Metabolic transformation in cancer Carcinogenesis, August 1, 2009; 30(8): 1269 - 1280. [Abstract] [Full Text] [PDF] D. R. Fels, J. Ye, A. T. Segan, S. J. Kridel, M. Spiotto, M. Olson, A. C. Koong, and C. Koumenis Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways Cancer Res., November 15, 2008; 68(22): 9323 - 9330. [Abstract] [Full Text] [PDF]

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