| 콜레스테롤 산화 생성물 7-Ketocholesterol에 의한
세포자멸사에 미치는 Extracellular
Signal-Regulated Kinase 억제의 효과 |
| 황정연, 이선화 한정호 김두응 이정수
a |
| 서울보훈병원 신경과, 중앙대학교 의과대학 약리학교실
a |
| Effect of Extracellular Signal-Regulated Kinase Inhibition on
Oxysterol 7-Ketocholesterol-Induced Apoptosis |
| Jung-Yun Hwang |
| Department of Neurology, Seoul Veterans Hospital, Seoul, Korea
Department of Pharmacology
a
, College of Medicine, Chung-Ang University, Seoul, Korea |
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| Abstract |
Background: Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury.
The extracellular-signal-regulated kinase (ERK) signaling pathway plays a crucial role in almost all cell functions,
including proliferation, differentiation, survival, and death. However, the effect of ERK inhibition on oxysterol-induced
apoptosis remains uncertain.
Methods: This study assessed the effect of ERK inhibition on the apoptotic effect of 7-ketocholesterol.
Results: Treatment with 7-ketocholesterol increased phosphorylated-ERK1/2 levels in differentiated PC12 cells, while
the total amount of ERK was not altered. 7-Ketocholesterol decreased Bid and Bcl-2 levels, increased Bax and p53 levels,
and promoted cytochrome c release, which elicits the activation of caspases (-8, -9, and -3), nuclear damage, and cell
death. ERK and farnesyltransferase inhibitors inhibited the 7-ketocholesterol-induced phosphorylation of ERK1/2,
activation of apoptosis-related proteins, and cell death in PC12 cells.
Conclusions: The ERK and farnesyltransferase inhibitors, which did not exhibit toxicity, may inhibit the 7-ketocholesterol
toxicity on differentiated PC12 cells by suppressing the activation of the caspase-8-dependent pathway as well as
activation of the mitochondria-mediated cell-death pathway, leading to the activation of caspases. The inhibition of ERK
may confer a beneficial protective effect against the neuronal cell injury induced by cholesterol oxidation products. Key Words: 7-Ketocholesterol, ERK inhibition, PC12 cells, Apoptosis-related proteins, Cell death |
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