title: eIF4F complex disruption causes protein synthesis inhibition during hypoxia in nerve growth factor (NGF)-differentiated PC12 cells.
abstract: Poor oxygenation (hypoxia) influences important physiological and pathological situations, including development, ischemia, stroke and cancer. Hypoxia induces protein synthesis inhibition that is primarily regulated at the level of initiation step. This regulation generally takes place at two stages, the phosphorylation of the subunit α of the eukaryotic initiation factor (eIF) 2 and the inhibition of the eIF4F complex availability by dephosphorylation of the inhibitory protein 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1). The contribution of each of them is mainly dependent of the extent of the oxygen deprivation. We have evaluated the regulation of hypoxia-induced translation inhibition in nerve growth factor (NGF)-differentiated PC12 cells subjected to a low oxygen concentration (0.1%) at several times. Our findings indicate that protein synthesis inhibition occurs primarily by the disruption of eIF4F complex through 4E-BP1 dephosphorylation, which is produced by the inhibition of the mammalian target of rapamycin (mTOR) activity via the activation of REDD1 (regulated in development and DNA damage 1) protein in a hypoxia-inducible factor 1 (HIF1)-dependent manner, as well as the translocation of eIF4E to the nucleus. In addition, this mechanism is reinforced by the increase in 4E-BP1 levels, mainly at prolonged times of hypoxia.
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, RyCIS, Madrid, Spain.
authors.forename: Macarena
authors.initials: M
authors.lastname: Hernández-Jiménez
authors.forename: M Irene
authors.initials: MI
authors.lastname: Ayuso
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Pérez-Morgado
authors.forename: Eva M
authors.initials: EM
authors.lastname: García-Recio
authors.forename: Alberto
authors.initials: A
authors.lastname: Alcázar
authors.forename: M Elena
authors.initials: ME
authors.lastname: Martín
authors.forename: Víctor M
authors.initials: VM
authors.lastname: González
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D015687:Cell Hypoxia; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D051381:Rats
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039562:Eukaryotic Initiation Factor-4F; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D000255:Adenosine Triphosphate; D020932:Nerve Growth Factor