title: Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis.
abstract: Disturbance of homeostasis within the endoplasmic reticulum (ER) lumen leads to the accumulation of unfolded and misfolded proteins. This results in the activation of an evolutionary conserved stress response termed ER stress that, if unresolved, induces apoptosis. Previously the Bcl-2 homology domain 3-Only Protein Puma was identified as a mediator of ER stress-induced apoptosis in neurons. In the search of alternative contributors to ER stress-induced apoptosis, a downregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 was noted during ER stress in both mouse cortical neurons and human SH-SY5Y neuroblastoma cells. Downregulation of Mcl-1 was associated with an upregulation of microRNA-29a (miR-29a) expression, and subsequent experiments showed that miR-29a targeted the 3'-untranslated region of the anti-apoptotic Bcl-2 family protein, Mcl-1. Inhibition of miR-29a expression using sequence-specific antagomirs or the overexpression of Mcl-1 decreased cell death following tunicamycin treatment, while gene silencing of Mcl-1 increased cell death. miR-29a did not alter the signalling branches of the ER stress response, rather its expression was controlled by the ER stress-induced transcription factor activating-transcription-factor-4 (ATF4). The current data demonstrate that the ATF4-mediated upregulation of miR-29a enhances the sensitivity of neurons to ER stress-induced apoptosis.
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Katie
authors.initials: K
authors.lastname: Nolan
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Walter
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Liam P
authors.initials: LP
authors.lastname: Tuffy
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Simone
authors.initials: S
authors.lastname: Poeschel
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Ross
authors.initials: R
authors.lastname: Gallagher
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haunsberger
authors.affiliation: Cancer Genetics, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Isabella
authors.initials: I
authors.lastname: Bray
authors.affiliation: Cancer Genetics, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Stallings
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Caoimhín G
authors.initials: CG
authors.lastname: Concannon
authors.affiliation: Centre for the Study of Neurological Disorders and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, 2, Ireland.
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C081452:Atf4 protein, mouse; C547014:MIRN29 microRNA, mouse; C579094:Mcl1 protein, mouse; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins; D051701:Activating Transcription Factor 4
keywords: BCL-2 proteins; cell death; cortical neurons; endoplasmic reticulum (ER) stress; microRNA