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J. Biol. Chem., Vol. 282, Issue 3, 1788-1796, January 19, 2007
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Nitric Oxide Modulates Oxygen Sensing by Hypoxia-inducible Factor 1-dependent Induction of Prolyl Hydroxylase 2*
From the Institut für Physiologie, Universität Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany
The transcription factor complex hypoxia-inducible factor 1 (HIF-1) plays a crucial role in cellular adaptation to low oxygen availability. O2-dependent HIF prolyl hydroxylases (PHDs) modify HIF-1
, which is sent to proteasomal degradation under normoxia. Reduced activity of PHDs under hypoxia allows stabilization of HIF-1 and induction of HIF-1 target gene expression. Like hypoxia, nitric oxide (NO) was found to inhibit normoxic PHD activity leading to HIF-1 accumulation. In contrast under hypoxia, NO reduced HIF-1 levels due to enhanced PHD activity. Herein, we studied the role of NO in regulating PHD expression and the consequences thereof for HIF-1 degradation. We report a biphasic response of HIF-1 and PHDs to NO treatment both under normoxia and hypoxia. In the early phase, NO inhibits PHD activity that leads to HIF-1 accumulation, whereas in the late phase, increased PHD levels reduce HIF-1. NO induces expression of PHD2 and -3 mRNA and protein under normoxia and hypoxia in a strictly HIF-1-dependent manner. NO-treated cells with elevated PHD levels displayed delayed HIF-1 accumulation and accelerated degradation of HIF-1 upon reoxygenation. Subsequent suppression of PHD2 and -3 expression using small interfering RNA revealed that PHD2 was exclusively responsible for regulating HIF-1 degradation under NO treatment. In conclusion, we identified the induction of PHD2 as an underlying mechanism of NO-induced degradation of HIF-1.
Received for publication, July 25, 2006 , and in revised form, October 2, 2006.
* This work was supported by Deutsche Forschungsgemeinschaft Grant Fa 225/20-1/2 (to J. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed. Tel./Fax: 49-201-723-4600/4648; E-mail: joachim.fandrey{at}uni-essen.de.
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