4.4 Article

Inhibition of palmitate-induced GADD34 expression augments apoptosis in mouse insulinoma cells (MIN6)

期刊

CELL BIOCHEMISTRY AND FUNCTION
卷 32, 期 5, 页码 445-452

出版社

WILEY-BLACKWELL
DOI: 10.1002/cbf.3036

关键词

GADD34; palmitate; salubrinal; endoplasmic reticulum stress; beta-cell; diabetes; islet

资金

  1. Swedish Society of Medicine
  2. Olle Engkvist Byggmastare Foundation
  3. Diabetes Research and Wellness Foundation
  4. Berth von Kantzow's Foundation
  5. Golje's memorial Foundation
  6. Eva and Oscar Ahren's Foundation
  7. Swedish Society for Medical Research
  8. JDRF (ECIT Islet for Basic Research program) [31-2008-413]

向作者/读者索取更多资源

Saturated fatty acids like palmitate induce endoplasmic reticulum(ER) stress in pancreatic beta-cells, an event linked to apoptotic loss of beta-cells in type 2 diabetes. Sustained activation of the ER stress response leads to expression of growth arrest and DNA damage-inducible protein 34 (GADD34), a regulatory subunit of protein phosphatase 1. In the present study, we have used small interfering RNA in order to knockdown GADD34 expression in insulin-producing MIN6 cells prior to induction of ER stress by palmitate and evaluated its consequences on RNA-activated protein kinase-like ER-localized eIF2alpha kinase (PERK) signalling and apoptosis. Salubrinal, a specific inhibitor of eukaryotic initiation factor 2 alpha (eIF2 alpha) dephosphorylation, was used as a comparison. Salubrinal treatment augmented palmitate-induced ER stress and increased GADD34 levels. Both GADD34 knockdown and salubrinal treatment potentiated the cytotoxic effects of palmitate as evidenced by increased DNA fragmentation and activation of caspase 3, with the fundamental difference that the former did not involve enhanced levels of GADD34. The data from this study suggest that sustained activation of PERK signalling and eIF2 alpha phosphorylation sensitizes insulin-producing MIN6 cells to lipoapoptosis independently of GADD34 expression levels. Copyright (C) 2014 John Wiley & Sons, Ltd.

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