HSP25 inhibits radiation-induced apoptosis through reduction of PKCdelta-mediated ROS production.
Since radiation-induced caspase-dependent apoptosis and ROS generation were partially prevented by HSP25 overexpression, similar to the treatment of control cells with antioxidant agents such as DPI and tiron, questions arise whether radiation-mediated ROS generation contributes to the apoptotic cell death, and also whether HSP25 overexpression can reduce ROS mediated apoptotic cell death. In the present study, radiation-induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential in Jurkat T cells were shown to be inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpressed, effects similar to the treatment of cells with the antioxidants were obtained, indicating that HSP25 suppressed radiation-induced mitochondrial alteration that resulted in apoptosis. Furthermore, activation of p38 MAP kinase by radiation was associated with radiation-induced cell death and ROS production and PKCdelta was an upstream molecule for p38 MAP kinase activation, ROS generation and subsequent caspase-dependent apoptotic events. However, in the HSP25 overexpressed cells, the above-described effects were blocked. In fact, radiation-induced membrane translocation of PKCdelta and tyrosine phosphorylation were inhibited by HSP25. Based on the above data, we suggest that HSP25 downregulates PKCdelta, which is a key molecule for radiation-induced ROS generation and mitochondrial-mediated caspase-dependent apoptotic events.
Lee
Yoon-Jin
YJ
Laboratory of Radiation Effect, Division of Radiation Biology, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea.
Lee
Dae-Hoon
DH
Cho
Chul-Koo
CK
Chung
Hee-Yong
HY
Bae
Sangwoo
S
Jhon
Gil-Ja
GJ
Soh
Jae-Won
JW
Jeoung
Doo-Il
DI
Lee
Su-Jae
SJ
Lee
Yun-Sil
YS
D017209:Apoptosis / Q000528:radiation effects*; D004789:Enzyme Activation; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases