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Comparative Study
. 2001 Oct 26;276(43):39805-11.
doi: 10.1074/jbc.M107689200. Epub 2001 Aug 20.

Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide

K B Sandau  1 , J Zhou, T Kietzmann, B Brüne
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Free article
Comparative Study

Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide

K B Sandau et al. J Biol Chem. .
Free article

Abstract

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-1alpha and -beta subunits, and stability regulation occurs via accumulation/degradation of HIF-1alpha 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-alpha (TNF-alpha) on HIF-1alpha regulation. For comparison, LLC-PK(1) 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-1alpha stabilization with differences in the time-dependent accumulation pattern, significant variations appeared with regard to signaling. With the use of a superoxide anion (O(2-)) generator, we established an O(2-)-sensitive pathway that blocked HIF-1alpha stabilization in response to NO and TNF-alpha while DFX- and PAO-evoked HIF-1alpha stabilization appeared O(2-)-insensitive. NO and TNF-alpha 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-alpha, PAO resembled a stimulus that induced a dysfunctional HIF-1 complex. These data indicate that diverse agonists activate HIF-1alpha under normoxic conditions by employing different signaling pathways.

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