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Kim W.-H.,National Institutes of Health and 194 Tongillo | Jang M.K.,Pusan National University | Kim C.H.,Pusan National University | Shin H.K.,Pusan National University | Jung M.H.,Pusan National University
Biochemical and Biophysical Research Communications | Year: 2011

Chronic endoplasmic reticulum (ER) stress leads to β-cell failure via reduction of pancreatic and duodenal homeobox-1 (PDX-1) activity, which contributes to the pathogenesis of type 2 diabetes. However, the exact mechanisms by which ER stress reduces PDX-1 activity in pancreatic β-cells are unclear. Previously, we showed that ATF3 downregulates PDX-1 gene expression in MIN6N8 pancreatic β-cells. Here, we investigated another role of ATF3 on the regulation of PDX-1 activity. ATF3 significantly inhibited PDX-1-stimulated transactivation of reporter plasmid containing promoters for PDX-1 binding element and the PDX-1 target gene glucokinase, which is dependent on C-terminal domain of ATF3. ATF3 interacted with PDX-1, and effectively inhibited p300-mediated transcriptional coactivation of the PBE-containing promoter, whereas C-terminal domain-deleted ATF3 did not inhibit the transcoactivation of p300. ATF3 decreased the interaction of p300 with PDX-1 in MIN6N8 cells coexpressing PDX-1 and ATF3. In addition, chromatin immunoprecipitation analysis demonstrated that both tunicamycin treatment and ATF3 overexpression inhibited the recruitment of p300 to PDX-1 on the insulin promoter in MIN6N8 cells. Taken together, these results suggest that ATF3 inhibits PDX-1-mediated transactivation through the inhibition of p300-stimulated coactivation, which may lead to β-cell dysfunction by ER stress. © 2011 Elsevier Inc. Source


Kim J.Y.,National Institutes of Health and 194 Tongillo | Song E.H.,National Institutes of Health and 194 Tongillo | Lee S.,National Institutes of Health and 194 Tongillo | Lim J.H.,National Institutes of Health and 194 Tongillo | And 4 more authors.
Cellular Signalling | Year: 2010

It is well established that the IFN-γ/STAT1 pathway plays an important role in the pancreatic β-cell apoptosis that is observed in STZ-induced type 1 diabetes; however, the upstream regulatory proteins involved have not been understood. Here, we investigated whether activating transcription factor 3 (ATF3) affects STAT1-mediated β-cell dysfunction and apoptosis in streptozotocin-treated mice. To this, STZ (80mg/kg, i.p.) was administered to wild-type and STAT1-/- or IFN-γ-/- mice for 5days and the mice were euthanized after 14days. STZ-induced β-cell dysfunction and apoptosis were associated with increased STAT1/IRF-1 and ATF3 expression and were correlated with elevated IFN-γ levels. Genetic depletion using IFN-γ-/- or STAT1-/- mice strongly inhibited the reduction of islet cell mass or insulin synthesis/secretion and the increase of β-cell apoptosis observed in STZ-treated wild-type mice. ATF3 overexpression, especially the C-terminal domain, strongly enhanced β-cell dysfunction and apoptosis by enhancing STAT1 activation and its accumulation, which were abolished with an ATF3-specific siRNA or C-terminal-deleted ATF3. The STZ induction of ATF3 was completely depleted in IFN-γ-/- mice, but not in STAT1-/- mice. Furthermore, STAT1 did not affect ATF3 expression, but STAT1 depletion or its inactivation inhibited STZ-induced ATF3 nuclear translocation and β-cell apoptosis. Interestingly, ATF3 also increased STAT1 transcription by directly binding to a putative binding region (-116 to -96bp) in the STAT1 promoter. Our results suggest that ATF3 functions as a potent upstream regulator of STAT1 and ATF3 may play a role in STZ-induced β-cell dysfunction by enhancing the steady state abundance of STAT1. © 2010 Elsevier Inc. Source

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