title: TRIB3 alters endoplasmic reticulum stress-induced β-cell apoptosis via the NF-κB pathway.
abstract: OBJECTIVE
  To examine the effect of TRIB3 on endoplasmic reticulum stress induced β-cell apoptosis and to investigate the mechanism with a specific emphasis on the role of NF-κB pathway.
  
  
  METHODS
  We investigated the effect of TRIB3 on ER stress-induced β-cell apoptosis in INS-1 cells and primary rodent islets. The potential role of TRIB3 in ER stress inducer thapsigargin (Tg)-induced β-cell apoptosis was assessed using overexpression and siRNA knockdown approaches. Inducible TRIB3 β-cells, regulated by the tet-on system, were used for sub-renal capsule transplantation in streptozotocin (STZ)-diabetic mice, to study the effect of TRIB3 on ER stress-induced β-cell apoptosis in vivo. Apoptosis was determined by TUNEL staining both in vivo and in vitro, while the molecular mechanisms of NF-κB activation were investigated.
  
  
  RESULTS
  TRIB3 was induced in ER-stressed INS-1 cells and rodent islets, and its overexpression was accompanied by increased β-cell apoptosis. Specifically, TRIB3 overexpression enhanced Tg-induced INS-1 derived β-cell apoptosis both in vitro and in sub-renal capsular transplantation animal model. Additionally, knockdown of Trib3 blocked Tg-induced apoptosis. Mechanistically, the induction of TRIB3 during ER stress resulted in the activation of NF-κB and aggravated INS-1 derived β-cell apoptosis, while inhibiting the NF-κB pathway significantly abrogated this response and prevented β-cell apoptosis, both in vitro and in sub-renal capsular transplantation animal model.
  
  
  CONCLUSIONS
  TRIB3 mediated ER stress-induced β-cell apoptosis via the NF-κB pathway.
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
authors.forename: Ni
authors.initials: N
authors.lastname: Fang
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Gynaecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Zai
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China. Electronic address: pengliang8028@163.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P. R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China. Electronic address: Lou.j@mail.com.
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D019284:Thapsigargin / Q000494:pharmacology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D034741:RNA, Small Interfering; C474830:TRB3 protein, mouse; D013311:Streptozocin; D019284:Thapsigargin
keywords: Apoptosis; ER stress; NF-κB; TRIB3; β-Cell