title: Hsp27 binding to the 3'UTR of bim mRNA prevents neuronal death during oxidative stress-induced injury: a novel cytoprotective mechanism.
abstract: Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cytoprotective and apoptosis-inducing signaling pathways. Cellular mechanisms that control apoptosis activation include the regulation of pro/antiapoptotic mRNAs through their 3'-untranslated region (UTR). This region holds binding elements for RNA-binding proteins, which can control mRNA translation. Here we demonstrate that heat shock protein 27 (Hsp27) prevents oxidative stress-induced cell death in cerebellar granule neurons by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2) correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition; however, it was associated with a specific increase in the levels of bim mRNA and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3'UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3'UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons.
authors.affiliation: Department of Physiology and Medical Physics and RCSI Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain daviddav@ucm.es prehn@rcsi.ie.
authors.forename: David
authors.initials: D
authors.lastname: Dávila
authors.affiliation: Department of Physiology and Medical Physics and RCSI Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jiménez-Mateos
authors.affiliation: Department of Physiology and Medical Physics and RCSI Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Mooney
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
authors.affiliation: Department of Physiology and Medical Physics and RCSI Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Department of Physiology and Medical Physics and RCSI Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland daviddav@ucm.es prehn@rcsi.ie.
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D006861:Hydrogen Peroxide