JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells

PLoS One. 2008 Aug 21;3(8):e3030. doi: 10.1371/journal.pone.0003030.


Cytokines contribute to pancreatic beta-cell apoptosis in type 1 diabetes (T1D) by modulation of beta-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated beta-cell dysfunction and death. The cytokines IL-1beta+IFN-gamma induced an early and transitory upregulation of JunB by NF-kappaB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary beta-cells. JunB knockdown beta-cells and junB(-/-) fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected beta-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis.

MeSH terms

  • 3T3 Cells
  • Adenoviridae
  • Animals
  • Apoptosis
  • Cell Death
  • Cells, Cultured
  • Endoplasmic Reticulum / physiology*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Deletion
  • Genetic Vectors
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Nitric Oxide / physiology
  • Proto-Oncogene Proteins c-jun / deficiency
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / physiology*
  • Rats
  • Rats, Wistar


  • Proto-Oncogene Proteins c-jun
  • Nitric Oxide