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      BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor 1α

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          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)-1α. 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-1α and mediates hypoxic cell death.

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          Most cited references34

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          A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

          We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
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            Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.

            A critical function of tumor suppressor p53 is the induction of apoptosis in cells exposed to noxious stresses. We report a previously unidentified pro-apoptotic gene, Noxa. Expression of Noxa induction in primary mouse cells exposed to x-ray irradiation was dependent on p53. Noxa encodes a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family of proteins; this member contains the BH3 region but not other BH domains. When ectopically expressed, Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9. We also demonstrate that blocking the endogenous Noxa induction results in the suppression of apoptosis. Noxa may thus represent a mediator of p53-dependent apoptosis.
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              Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.

              Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine), whereas cycloheximide blocked induction of glycolytic RNAs and HIF-1 activity. Oligonucleotides from the ALDA, PGK1, enolase 1, lactate dehydrogenase A, and phosphofructokinase L (PFKL) genes, containing sequences similar to the HIF-1 binding site in the erythropoietin enhancer, specifically bound HIF-1 present in crude nuclear extracts or affinity-purified preparations. Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia that underlie cellular and systemic oxygen homeostasis.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                5 January 2004
                : 199
                : 1
                : 113-124
                Affiliations
                [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
                Author notes

                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@ 123456khu.ac.kr

                Article
                20030613
                10.1084/jem.20030613
                1887730
                14699081
                694489c6-fa21-4b4e-a468-da2bfcc83bb2
                Copyright © 2004, The Rockefeller University Press
                History
                : 15 April 2003
                : 6 October 2003
                Categories
                Article

                Medicine
                noxa,apoptosis,ros,hypoxia,hif-1α
                Medicine
                noxa, apoptosis, ros, hypoxia, hif-1α

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