The Journal of Experimental Medicine
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Published online 29 December 2003 doi:10.1084/jem.20030613
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 1, 113-124
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BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor 1{alpha}

Jee-Youn Kim1, Hyun-Jong Ahn2, Jong-Hoon Ryu3, Kyoungho Suk4 and Jae-Hoon Park1

1 Department of Pathology and Medical Science and Engineering Research Center for Reactive Oxygen Species, College of Medicine
2 Department of Microbiology, College of Medicine
3 Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea
4 Department of Anatomy and Neurobiology, College of Medicine, Gyeongsang National University, Jinju, Kyungnam 660-751, Korea

Address correspondence to Jae-Hoon Park, Department of Pathology, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-Koo, Seoul 130-701, Korea. Phone: 82-2-961-0533; Fax: 82-2-960-2871; email: jhpark{at}khu.ac.kr

Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes, which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Using polymerase chain reaction–based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1{alpha}. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1{alpha} and mediates hypoxic cell death.

Key Words: Noxa • HIF-1{alpha} • hypoxia • apoptosis • ROS

Abbreviations used in this paper: AS, antisense; DCF-DA, 2', 7'-dichlorofluorescein diacetate; EMSA, electrophoretic mobility shift assay; HIF-1{alpha}, hypoxia-inducible factor 1 {alpha}; HRE, hypoxia-responsive element; MCAO, middle cerebral artery occlusion; NAC, N-acetylcysteine; p53-CBS, p53 consensus binding sequence; PI, propidium iodide; ROS, reactive oxygen species; SE, sense; SL-O, streptolysin-O; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling.


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