p73에 의한 세포사멸에서 p19Ras 의 역할에 대한 연구: p19Ras 에 의한 세포사멸에 대한 활성기산소의 역할

초록

Purpose : We have recently found that p73 and p19Ras were highly expressed in the development of diabetes, but the exact roles of p19Ras and p73 involved in pancreatic β cell apoptosis remain unclear. Methods : Using type I diabetes mice induced by STZ administaration or pancreatic β cell treated with chronic high glucose, we have investigated the mechanisms involved in the development of diabetes through pancreatic β-cell apoptosis. Results : p19Ras and p73 were highly expressed in STZ-injected mice and chronic high glucose-treated MIN6N8 cells, correlated with the induction of pancreatic β cell apoptosis. However, the levels of insulin and ATP was significantly decreased in both models. The expression of p73 and p19Ras was correlated with AMPK phosphorylation induced by chronic high glucose, which was potentiated by wild type AMPK overexpression, but abrogated by AMPK K45R. These results were confirmed by that AMPK inhibitor compound C significantly decreased the expression of p73 and p19Ras induced by chronic high glucose. Interestingly, GST-AMPK directly interacts with p73α, not with p73β, and specifically p73α constructs including C-terminal SAM domain and we have confirmed that activated AMPK was required for these interactionin in vitro and in vivo. Activated AMPK enhanced the stabilities of p19Ras and p73 by inhibiting ubiquitination. We have obtained the same results using islet cells isolated from mice. Conclusions : Our data demonstrate that p19Ras and p73 plays an important roles in the development of diabetes and especially activated AMPK was essential to the regulation of pancreatic β-cell apoptosis and development of diabetes.

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