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- Title
Regulation of MafA Expression in Pancreatic β-cells under Diabetic Condition.
- Authors
Matsuoka, Taka-Aki; Kaneto, Hideaki; Miyatsuka, Takeshi; Kato, Ken; Matsuhisa, Munehide; Yamasaki, Yoshimitsu
- Abstract
Islet β cells loose its ability to synthesize insulin under diabetic condition at least partially due to decreased activity of insulin transcription factors including MafA. Although in vitro study showed reactive oxygen species generated by high glucose decreased the expression of MafA, its underlying mechanism is still unclear. Our objective is to analyze the possible mechanism by which MafA is affected in diabetic β cells, Immunohistochemistry revealed that protein level of MafA was decreased in the islets of db/db mice but that expression of c-Jun, which is up-regulated by reactive oxygen species, was increased contrastively. Co-staining of those factors in islets of db/db mice clearly showed the lower expression of MafA and insulin in the c-Jun positive cells. Consistent with these results, co-transfection of c-Jun expression vector with insulin reporter plasmid into MIN6 β cell line decreased the insulin promoter activity to 25% as reported previously. Adenoviral overexpression of c-Jun in MIN6 cells also markedly and selectively decreased MafA on the analysis of both western blotting and immunocytochmistry. On the other hand, putting mutation in basic region or transactivation domain of c-Jun mined its effects on MafA and insulin. Importantly, MafA overexpression restored the insulin promoter activity and insulin protein amount suppressed by c-Jun overexpression on reporter gene analysis and immunocytochemistry, respectively. These results indicate that decreased insulin synthesis induced by c-Jun is principally mediated by suppression of MafA activity. Interestingly, c-Jun had almost no effects on the level of MafAmRNA. Furthermore, MafA promoter activity using reporter plasmids including various length of MafA enhancer and promoter region was not affected by c-Jun. Thus, we conclude that augmented expression of c-Jun in diabetic islets decreases MafA activity followed by reduced insulin synthesis, and that MafA expression is regulated by c-Jun mainly at the post-transcriptional level.
- Subjects
GENETIC regulation; TRANSCRIPTION factors; PANCREATIC beta cells; GENETICS of diabetes; INSULIN synthesis; OXYGEN in the body; PROMOTERS (Genetics); LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA429
- ISSN
0012-1797
- Publication type
Article