title: Musashi mediates translational repression of the Drosophila hypoxia inducible factor.
abstract: Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3' UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Agustina P
authors.identifier: 0000-0002-4808-8254
authors.initials: AP
authors.lastname: Bertolin
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Maximiliano J
authors.initials: MJ
authors.lastname: Katz
authors.affiliation: Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata, Niigata 951-8510, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE, UBA-CONICET), Ciudad Universitaria, Pabellón 2, Buenos Aires (C1428EHA), Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires (C1428EHA), Argentina.
authors.forename: Berta
authors.initials: B
authors.lastname: Pozzi
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Julieta M
authors.initials: JM
authors.lastname: Acevedo
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Dalmiro
authors.initials: D
authors.lastname: Blanco-Obregón
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Lautaro
authors.initials: L
authors.lastname: Gándara
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sorianello
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE, UBA-CONICET), Ciudad Universitaria, Pabellón 2, Buenos Aires (C1428EHA), Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires (C1428EHA), Argentina.
authors.forename: Anabella
authors.initials: A
authors.lastname: Srebrow
authors.affiliation: Instituto Leloir, Patricias Argentinas 435, Buenos Aires (1405), Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires (C1428EHA), Argentina pwappner@leloir.org.ar.
authors.forename: Pablo
authors.initials: P
authors.lastname: Wappner
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D056426:Genetic Loci; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008322:Mammals; D008954:Models, Biological; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014132:Trachea / Q000254:growth & development; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C100429:Sima protein, Drosophila; C088623:msi protein, Drosophila