title: GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition.
abstract: BACKGROUND
  Proteasome inhibition has been proven to be a promising therapeutic strategy in cancer clinical treatment. Inhibition of proteasome leads to failure of amino acid homeostasis, which causes cell death via activation of various mechanisms.
  
  
  METHODS
  To investigate the role of GADD34 in cell death following proteasome inhibition, we treated WT MEF and GADD34 KO MEF with MG132 and various analyses were performed, including PI staining, western blot, immunofluorescence and ROS production.
  
  
  RESULTS
  Expression of GADD34 dramatically enhanced MG132-induced cell death via protein synthesis. GADD34 decreased phosphorylated eIF2α and increased ROS production and the levels of ubiquinated protein. Importantly, we found that accumulation of autophagy following MG132-treatment facilitated cell death in MEF.
  
  
  CONCLUSIONS
  GADD34 plays a vital role in promoting cell death following proteasome inhibition via enhancing protein synthesis to activate death-associated mechanisms, including ER stress, ROS production and autophagy formation.
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Lintao
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nishio
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan Department of Food Science and Nutrition, Nagoya Women's University, Nagoya, Aichi, Japan isobe@nagoya-wu.ac.jp.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Isobe
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D007976:Leupeptins / Q000494:pharmacology*; D051379:Mice; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015852:Eukaryotic Initiation Factor-2; D007976:Leupeptins; D017382:Reactive Oxygen Species; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: GADD34; autophagy; cell death; eIF2α; proteasome inhibition