Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells.
Cisplatin induces apoptosis in a variety of cell types. However, the signaling pathway of cisplatin-induced apoptosis in renal epithelial cells is poorly understood. The present study was undertaken to determine the role of the extracellular signal-regulated kinase (ERK) in cisplatin-induced apoptosis of renal epithelial cells using opossum kidney cells. Cisplatin at 50 microM induced apoptosis in a time-dependent manner. Cisplatin treatment caused sustained activation of ERK1/2, which was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2. Transient transfection of cells with constitutive active MEK1 increased the cisplatin-induced apoptosis, whereas that with a dominant-negative mutant of MEK1 decreased it. Cisplatin induced an increase in Bax expression, mitochondrial membrane depolarization, mitochondrial cytochrome c release and caspase-3 activation, and these changes were prevented by the MEK inhibitor. These results suggested that (1) the ERK1/2 activation is required for the cisplatin-induced apoptosis of renal epithelial cells; and (2) ERK1/2 mediates the mitochondria-dependent apoptotic signaling by acting upstream of Bax expression.
Kim
Yong Keun
YK
Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Kim
Hyun Ju
HJ
Kwon
Chae Hwa
CH
Kim
Jae Ho
JH
Woo
Jae Suk
JS
Jung
Jin Sup
JS
Kim
Jong Min
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009893:Opossums / Q000502:physiology*; D014162:Transfection
D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D053148:Caspase 3; D020169:Caspases; D006690:Bisbenzimidazole; D002945:Cisplatin