Inhibition of ROS Production by HSP25 : (Involvement of PKCdelta Activity)

다국어 초록 (Multilingual Abstract)

Since radiation induced caspase-dependent apoptosis and ROS generation was partially prevented by HSP25 overexpresson, similar to when treatment of control cells with antioxidant agents, such as DPI and Tiron, questions of whether radiation-mediated ROS generation contributes to the apoptotic cell death and, if so, of whether HSP25 overexpression can reduce ROS mediated apoptotic cell death were examined. Radiation induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential were shown in control cells, and these processes were inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpresseed, effects similar to treatment of cells with the antioxidants were shown, indicating that HSP25 suppressed radiation induced mitochondrial alteration which resulted in apoptosis. Employing dominant-negative p38 MAP kinase which inhibited ROS generation, cytochrome c release, and caspase dependent apoptotic cell death, we found that the radiation-induced cell death and ROS production were associated with p38 MAP kinase activation. Furthermore, rottlerin, a specific inhibitor of PKCdelta which is an upstream molecules, reduced p38 MAP kinase activity, ROS generation and subsequent caspase-dependent apoptotic events. However, in HSP25 overexpressed cell, the above effects were blocked; PKCdelta and p38 MAP kinase activity were inhibited. In fact, radiation-induced membrane translocation of PKCdelta and tyrosin phosphorylation were inhibited by HSP25. Base on the above data, we suggest that HSP25 downregulates PKCdelta which a key molecule for radiation induced ROS generation and mitochondrial mediated caspase dependent apoptotic events.