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J. Biol. Chem., Vol. 280, Issue 6, 4321-4328, February 11, 2005

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Ca²⁺/Calmodulin Kinase-dependent Activation of Hypoxia Inducible Factor 1 Transcriptional Activity in Cells Subjected to Intermittent Hypoxia^*

Guoxiang Yuan, Jayasri Nanduri, C. Raman Bhasker¶, Gregg L. Semenza||, and Nanduri R. Prabhakar**

From the Departments of Physiology & Biophysics, Pathology, and ^¶Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, and the ^||Program in Vascular Cell Engineering and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Intermittent hypoxia (IH) occurs in many pathological conditions. However, very little is known about the molecular mechanisms associated with IH. Hypoxia-inducible factor 1 (HIF-1) mediates transcriptional responses to continuous hypoxia. In the present study, we investigated whether IH activates HIF-1 and, if so, which signaling pathways are involved. PC12 cells were exposed to either to 20% O₂ (non-hypoxic control) or to 60 cycles consisting of 30 s at 1.5% O₂, followed by 4 min at 20% O₂ (IH). Western blot analysis revealed significant increases in HIF-1 protein in nuclear extracts of cells subjected to IH. Expression of a HIF-1-dependent reporter gene was increased 3-fold in cells subjected to IH. Although IH induced the activation of ERK1, ERK2, JNK, PKC-, and PKC-, inhibitors of these kinases and of phosphatidylinositol 3-kinase did not block HIF-1-mediated reporter gene expression induced by IH, indicating that signaling via these kinases was not required. In contrast, addition of the intracellular Ca²⁺ chelator BAPTA-AM or the Ca²⁺/calmodulin-dependent (CaM) kinase inhibitor KN93 blocked reporter gene activation in response to IH. CaM kinase activity was increased 5-fold in cells subjected to IH. KN 93 prevented IH-induced transactivation mediated by HIF-1, and its coactivator p300, which was phosphorylated by CaM kinase II in vitro. Expression of the HIF-1-regulated gene encoding tyrosine hydroxylase was induced by IH and this effect was blocked by KN93. These observations suggest that IH induces HIF-1 transcriptional activity via a novel signaling pathway involving CaM kinase.

Received for publication, July 8, 2004 , and in revised form, November 19, 2004.

^* This work was supported in part by Public Health Service Grants P01-HL-25830 (to N. R. P.) and R01-HL-55338 (to G. L. S.) from the NHLBI, National Institutes of Health. 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.

^** To whom correspondence should be addressed: Dept. of Physiology & Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-8636; Fax: 216-368-1693; E-mail: nrp{at}po.cwru.edu.

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