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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3492-3493. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weidemann, A. Articles by Johnson, R. S. Search for Related Content PubMed Articles by Weidemann, A. Articles by Johnson, R. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Comment on Köditz et al, page 3610 A wrinkle in the unfolding of hypoxic response: HIF and ATF4 Alexander Weidemann, and Randall S. Johnson UNIVERSITY OF CALIFORNIA, SAN DIEGO Köditz et al describe the interaction of activating transcription factor-4 (ATF4) with the HIF hydroxylase PHD3, suggesting that oxygen-dependent regulatory pathways mediated by PHDs might not be confined to the HIF system. Hypoxia is a dynamic feature of ischemic disease and the tumor microenvironment. Survival pathways help cells adapt and overcome the hypoxic stress. The hypoxia-inducible factor (HIF) is the master regulator of the cellular adaptation to hypoxia.1 In hypoxia, the /β heterodimeric HIF complex induces transcription of target genes such as EPO, Glut-1, VEGF, and iNOS. Under normoxic conditions the von Hippel-Lindau (VHL) tumor suppressor protein binds the HIF- subunits, which leads to rapid proteasomal degradation. Essential for binding of VHL to the HIF- subunit is an oxygen-dependent posttranslational hydroxylation. This reaction is catalyzed by 3 oxygenases termed PHD1, PHD2, and PHD3 (PHD: prolyl hydroxylase domain enzymes), which are dioxygenases belonging to the 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenase superfamily.2 Prolyl hydroxylation through PHDs, and also asparagyl hydroxylation by the factor inhibiting HIF (FIH), has been shown to link cellular oxygen availabilty to the transcriptional response of the HIF system. Apart from HIF-regulated adaptation processes, several HIF-independent pathways exist to sustain oxygen deprivation. Recent evidence suggests that hypoxia activates components of the unfolded protein response (UPR). The stress-responsive activating transcription factor-4 (ATF4) is a downstream UPR gene that is up-regulated by a variety of stimuli such as hypoxia/anoxia, ER stress, and metabolic and oxidative stress. ATF4 can function as a transcriptional activator of UPR genes but has also been implicated in cellular defense processes. Studies in transgenic animals indicate that ATF4 is required for skeletal and eye development, cellular proliferation, and hematopoiesis.3 Moreover, ATF4 has been observed in greater levels in tumors than in normal tissue, suggesting that ATF4 signaling and the UPR as a whole are active in hypoxic areas of tumors and might regulate processes relevant to cancer progression.4 As Köditz and coworkers now demonstrate, the HIF prolyl hydroxylase PHD3 interacts with ATF4, thus establishing a link between the 2 adaptive systems. They convincingly show that ATF4 binds to PHD3 and that ATF4 protein stability is increased by PHD inhibition or hypoxia. Further characterization of the interaction identified a proline-rich domain in ATF4, which is important for oxygen-dependent degradation. This process does not involve VHL. But the molecular mechanism of the posttranslational modification of ATF4 by PHD3 is not fully understood yet, and it remains elusive whether hydroxylation of the prolines or the binding of other factors influence the stability of ATF4. The functional significance of the findings of Köditz and colleagues lies in the demonstration of a molecular link between 2 central systems of cellular adaptive processes to stress. It raises the possibility that hydroxylation, and ultimately function, of HIF- or HIF target genes might be influenced by this novel role for PHD3, and might as well have impact on the general understanding of cell-fate decisions in hypoxia. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732.[CrossRef][Medline] [Order article via Infotrieve] Schofield CJ and Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5:343–354.[CrossRef][Medline] [Order article via Infotrieve] Ameri K and Harris AL. Activating transcription factor 4. Int J Biochem Cell Biol 2007;. Koumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 2006; 6:55–69.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor Jens Köditz, Jutta Nesper, Marieke Wottawa, Daniel P. Stiehl, Gieri Camenisch, Corinna Franke, Johanna Myllyharju, Roland H. Wenger, and Dörthe M. Katschinski Blood 2007 110: 3610-3617. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weidemann, A. Articles by Johnson, R. S. Search for Related Content PubMed Articles by Weidemann, A. Articles by Johnson, R. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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