Protection of pancreatic beta-cells from various stress conditions is mediated by DJ-1.
Pancreatic beta-cells are vulnerable to multiple stresses, leading to dysfunction and apoptotic death. Deterioration in beta-cells function and mass is associated with type 2 diabetes. Comparative two-dimensional gel electrophoresis from pancreatic MIN6 cells that were maintained at varying glucose concentrations was carried out. An induced expression of a protein spot, detected in MIN6 cells experiencing high glucose concentration, was identified by mass spectrometry as the oxidized form of DJ-1. DJ-1 (park7) is a multifunctional protein implicated in familial Parkinsonism and neuroprotection in response to oxidative damage. The DJ-1 protein and its oxidized form were also induced following exposure to oxidative and endoplasmic reticulum stress in MIN6 and betaTC-6 cells and also in mouse pancreatic islets. Suppression of DJ-1 levels by small interfering RNA led to an accelerated cell death, whereas an increase in DJ-1 levels by adenovirus-based infection attenuated cell death induced by H(2)O(2) and thapsigargin in beta-cell lines and mouse pancreatic islets. Furthermore, DJ-1 improved regulated insulin secretion under basal as well as oxidative and endoplasmic reticulum stress conditions in a dose-dependent manner. We identified TFII-I (Gtf2i) as DJ-1 partner in the cytosol, whereas the binding of TFII-I to DJ-1 prevented TFII-I translocation to the nucleus. The outcome was attenuation of the stress response. Our results suggest that DJ-1 together with TFII-I operate in concert to cope with various insults and to sustain pancreatic beta-cell function.
Department of Biological Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Alex
A
Inberg
Michal
M
Linial
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D054464:Peroxiredoxins; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D019473:Transcription Factors, TFII / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; C486330:Gtf2i protein, mouse; D006360:Heat-Shock Proteins; D007328:Insulin; D015513:Oncogene Proteins; D019473:Transcription Factors, TFII; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D005947:Glucose