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The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells.

Publication Date
DOI: 10.1242/10.1242/jcs.00356
  • Adaptor Proteins
  • Signal Transducing
  • Animals
  • Apoptosis/Drug Effects
  • Blotting
  • Western
  • Carrier Proteins/Genetics
  • Carrier Proteins/Metabolism
  • Cell Line
  • Cells
  • Cultured
  • Cytokines/Pharmacology
  • Dna Fragmentation/Drug Effects
  • Genotype
  • Interferon-Gamma/Pharmacology
  • Interleukin-1/Pharmacology
  • Islets Of Langerhans/Cytology
  • Islets Of Langerhans/Drug Effects
  • Jnk Mitogen-Activated Protein Kinases
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases/Drug Effects
  • Mitogen-Activated Protein Kinases/Metabolism
  • Nuclear Proteins/Genetics
  • Nuclear Proteins/Metabolism
  • Rats
  • Rats
  • Wistar
  • Trans-Activators/Genetics
  • Trans-Activators/Metabolism
  • Transfection
  • Tumor Necrosis Factor-Alpha/Pharmacology
  • Biology


In insulin-secreting cells, cytokines activate the c-Jun N-terminal kinase (JNK), which contributes to a cell signaling towards apoptosis. The JNK activation requires the presence of the murine scaffold protein JNK-interacting protein 1 (JIP-1) or human Islet-brain 1(IB1), which organizes MLK3, MKK7 and JNK for proper signaling specificity. Here, we used adenovirus-mediated gene transfer to modulate IB1/JIP-1 cellular content in order to investigate the contribution of IB1/JIP-1 to beta-cell survival. Exposure of the insulin-producing cell line INS-1 or isolated rat pancreatic islets to cytokines (interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta) induced a marked reduction of IB1/JIP-1 content and a concomitant increase in JNK activity and apoptosis rate. This JNK-induced pro-apoptotic program was prevented in INS-1 cells by overproducing IB1/JIP-1 and this effect was associated with inhibition of caspase-3 cleavage. Conversely, reducing IB1/JIP-1 content in INS-1 cells and isolated pancreatic islets induced a robust increase in basal and cytokine-stimulated apoptosis. In heterozygous mice carrying a selective disruption of the IB1/JIP-1 gene, the reduction in IB1/JIP-1 content in happloinsufficient isolated pancreatic islets was associated with an increased JNK activity and basal apoptosis. These data demonstrate that modulation of the IB1-JIP-1 content in beta cells is a crucial regulator of JNK signaling pathway and of cytokine-induced apoptosis.

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