Journal of Biological Chemistry
Volume 276, Issue 43, 26 October 2001, Pages 39805-39811
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MECHANISMS OF SIGNAL TRANSDUCTION
Regulation of the Hypoxia-inducible Factor 1α by the Inflammatory Mediators Nitric Oxide and Tumor Necrosis Factor-α in Contrast to Desferroxamine and Phenylarsine Oxide*

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Hypoxic/ischemic conditions provoke activation of the hypoxia-inducible factor-1 (HIF-1), which functions as a transcription factor. HIF-1 is composed of the HIF-1α and -β subunits, and stability regulation occurs via accumulation/degradation of HIF-1α with the notion that a prolyl hydroxylase accounts for changes in protein level. In addition, there is evidence that HIF-1 is up-regulated by diverse agonists during normoxia. We investigated the impact of inflammatory mediators nitric oxide (NO) and tumor necrosis factor-α (TNF-α) on HIF-1α regulation. For comparison, LLC-PK1 cells were exposed to hypoxia, stimulated with desferroxamine (DFX, known to mimic hypoxia), and the thiol-cross-linking agent phenylarsine oxide (PAO). Although all stimuli elicited HIF-1α stabilization with differences in the time-dependent accumulation pattern, significant variations appeared with regard to signaling. With the use of a superoxide anion (O2) generator, we established an O2-sensitive pathway that blocked HIF-1α stabilization in response to NO and TNF-α while DFX- and PAO-evoked HIF-1α stabilization appeared O2-insensitive. NO and TNF-α signaling required phosphorylation events, especially activation of the phosphatidylinositol 3-kinase/Akt, which is in contrast to DFX and PAO. Based on HIF-1-dependent luciferase reporter gene analysis, it was found that, in contrast to NO and TNF-α, PAO resembled a stimulus that induced a dysfunctional HIF-1 complex. These data indicate that diverse agonists activate HIF-1α under normoxic conditions by employing different signaling pathways.

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Published, JBC Papers in Press, August 20, 2001, DOI 10.1074/jbc.M107689200

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This work was supported by Deutsche Forschungsgemeinschaft Grants BR999, SFB423/A5, and EC Grant QLK6-2000-00064 (to B. B.) and Deutsche Forschungsgemeinschaft Grant SFB 402/A1 (to T. K.)The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.