title: Endoplasmic reticulum stress stimulates p53 expression through NF-κB activation.
abstract: BACKGROUND
  Induction of apoptosis by endoplasmic reticulum (ER) stress is implicated as the major factor in the development of multiple diseases. ER stress also appears to be a potentially useful major response to many chemotherapeutic drugs and environmental chemical compounds. A previous study has indicated that one major apoptotic regulator, p53, is significantly increased in response to ER stress, and participates in ER stress-induced apoptosis. However, the regulators of p53 expression during ER stress are still not fully understood.
  
  
  RESULTS
  In this report, we demonstrate that induction of p53 expression is mediated through NF-κB signaling pathways during ER stress in MCF-7 cells. Tunicamycin or brefeldin A, two ER stress inducers, increased p53 expression in MCF-7 and Hela cells. We found p53 nuclear localization, activity, and phosphorylation at serine 15 on p53 increased during ER stress. Nuclear translocation of NF-κB and activity of NF-κB were also observed during ER stress. ER stress-induced p53 expression was significantly inhibited by coincubation with the NF-κB inhibitor, Bay 11-7082 and downregulation of NF-κB p65 expression. The role of p53 in mediating Brefeldin A-induced apoptosis was also investigated. Induction of p53 expression by Brefeldin A was correlated to Brefeldin A-induced apoptosis. Furthermore, downregulation of p53 expression by p53 siRNA significantly reduced Brefeldin A-induced apoptosis in MCF-7 cells.
  
  
  CONCLUSIONS
  Taken together, NF-κB activation and induction of p53 expression is essential for ER stress-induced cell death which is important for therapeutic effects of clinical cancer drugs. Our results may provide insight into the mechanism of cancer chemotherapy efficacy that is associated with induction of ER stress.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Wan-Chi
authors.initials: WC
authors.lastname: Lin
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chuang
authors.forename: Yung-Sheng
authors.initials: YS
authors.lastname: Chang
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Yen-Ni
authors.initials: YN
authors.lastname: Teng
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.forename: Clay C C
authors.initials: CC
authors.lastname: Wang
authors.forename: Kuan-Han
authors.initials: KH
authors.lastname: Lee
authors.forename: Jui-Hsiang
authors.initials: JH
authors.lastname: Hung
mesh_terms: D017209:Apoptosis; D020126:Brefeldin A / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D020126:Brefeldin A; D003513:Cycloheximide; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3