Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells.
Glutamic acid decarboxylase (GAD) is one major autoantigen involved in the pathogenesis of autoimmune insulin dependent diabetes mellitus (IDDM). Molecular mechanisms regulating GAD expression in pancreatic beta cell are still ill-defined. Here we investigated the effect of streptozotocin (STZ), a beta cell-specific toxin, on the expression of GAD67 in MIN6N8a mouse beta cell. A 5-6-fold increase in the expression GAD67 mRNA was found in cells treated with 1.25mM STZ for 12h. Addition of NAD+ to the incubation medium slightly reduced the STZ-induced upregulation of GAD67. STZ increased p53 levels that in turn up-modulated GAD67 expression. This effect was abolished upon addition of the antioxidant N-acetyl cysteine (NAC). STZ also activated NF-kappaB and blockade of NF-kappaB activation inhibited the STZ-mediated upregulation of GAD67 expression. As a whole these data show that low dose of STZ up-regulates GAD67 expression in mouse bate cell and that NF-kappaB activation through oxidative stress plays a key role in this phenomenon. They also suggest that various stimuli promoting NF-kappaB activation may up-regulate expression of GAD autoantigen in mouse beta cells.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000209:etiology; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007515:Islets of Langerhans / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D001324:Autoantigens; D007527:Isoenzymes; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D009243:NAD; D013311:Streptozocin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1