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경희대학교 의과대학 병리학교실

J. Exp. Med., Volume 199, Number 1, 113-124 BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor 1α

Abstract

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

Abstract:
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. 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 and mediates hypoxic cell death.

Key Words: Noxa, HIF-1, hypoxia, apoptosis, ROS

Abbreviations used in this paper: AS, antisense; DCF-DA, 2'', 7''-dichlorofluorescein diacetate; EMSA, electrophoretic mobility shift assay; HIF-1, hypoxia-inducible factor 1 ; 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.

논문정보

형식Research article
게재일2004년 01월 (BRIC 등록일 )
연구진국내 연구진
분야
피인용횟수120회 이상 인용된 논문 (상위피인용논문 등록일 2015-03-19)

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