title: Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis.
abstract: Hypoxia is an important factor that elicits numerous physiological and pathological responses. One of the major gene expression programs triggered by hypoxia is mediated through hypoxia-responsive transcription factor hypoxia-inducible factor 1 (HIF-1). Here, we report the identification and cloning of a novel HIF-1-responsive gene, designated RTP801. Its strong up-regulation by hypoxia was detected both in vitro and in vivo in an animal model of ischemic stroke. When induced from a tetracycline-repressible promoter, RTP801 protected MCF7 and PC12 cells from hypoxia in glucose-free medium and from H(2)O(2)-triggered apoptosis via a dramatic reduction in the generation of reactive oxygen species. However, expression of RTP801 appeared toxic for nondividing neuron-like PC12 cells and increased their sensitivity to ischemic injury and oxidative stress. Liposomal delivery of RTP801 cDNA to mouse lungs also resulted in massive cell death. Thus, the biological effect of RTP801 overexpression depends on the cell context and may be either protecting or detrimental for cells under conditions of oxidative or ischemic stresses. Altogether, the data suggest a complex type of involvement of RTP801 in the pathogenesis of ischemic diseases.
authors.affiliation: Quark Biotech, Inc., Cleveland, Ohio 44106, USA.
authors.forename: Tzipora
authors.initials: T
authors.lastname: Shoshani
authors.forename: Alexander
authors.initials: A
authors.lastname: Faerman
authors.forename: Igor
authors.initials: I
authors.lastname: Mett
authors.forename: Elena
authors.initials: E
authors.lastname: Zelin
authors.forename: Tamar
authors.initials: T
authors.lastname: Tenne
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gorodin
authors.forename: Yana
authors.initials: Y
authors.lastname: Moshel
authors.forename: Shlomo
authors.initials: S
authors.lastname: Elbaz
authors.forename: Andrei
authors.initials: A
authors.lastname: Budanov
authors.forename: Ayelet
authors.initials: A
authors.lastname: Chajut
authors.forename: Hagar
authors.initials: H
authors.lastname: Kalinski
authors.forename: Iris
authors.initials: I
authors.lastname: Kamer
authors.forename: Ada
authors.initials: A
authors.lastname: Rozen
authors.forename: Orna
authors.initials: O
authors.lastname: Mor
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
authors.forename: Dena
authors.initials: D
authors.lastname: Leshkowitz
authors.forename: Paz
authors.initials: P
authors.lastname: Einat
authors.forename: Rami
authors.initials: R
authors.lastname: Skaliter
authors.forename: Elena
authors.initials: E
authors.lastname: Feinstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001483:Base Sequence; D002454:Cell Differentiation; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017403:In Situ Hybridization; D008081:Liposomes / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D020521:Stroke / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C000632146:Ddit4 protein, rat; C450979:Ddit4l protein, mouse; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; D006861:Hydrogen Peroxide