Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-α in rat mesangial cells

被引:236
|
作者
Guo, YL [1 ]
Baysal, K [1 ]
Kang, B [1 ]
Yang, LJ [1 ]
Williamson, JR [1 ]
机构
[1] Univ Penn, Dept Biochem & Biophys, Goddard Labs 601, Sch Med, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.273.7.4027
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rat mesangial cells are normally resistant to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis, In this report we show that the cells can be made susceptible to the apoptotic effect of TNF-alpha when pretreated with actinomycin D, cycloheximide, or vanadate. c-Jun N-terminal protein kinase (JNK) has been thought to mediate apoptotic processes elicited by some stimuli, but its involvement in TNF-alpha-induced apoptosis has been controversial, JNK activation was investigated under conditions where the mesangial cells were either resistant or susceptible to TNF-alpha-induced apoptosis, TNF-alpha alone stimulated a single transient JNK activity peak, However, when the cells were pretreated with actinomycin D or cycloheximide, TNF-alpha stimulated a second sustained JNK activity peak. When the cells were pretreated with the phosphatase inhibitor vanadate, TNF-alpha-induced JNK activation was greatly prolonged, In all three cases, a sustained JNK activation was associated with the initiation of apoptosis. Our data suggest that a sustained activation of JNK induced by these reagents may be associated with blocking the expression of a phosphatase that inactivates JNK, Further studies reveal that the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was induced by TNF-alpha, indicating that MKP-1 may be involved in protecting the cells from apoptosis by preventing a prolonged activation of JNK under normal conditions. Additional studies showed that extracellular signal-regulated protein kinase activation stimulated by TNF-alpha was unlikely to contribute to the resistance of mesangial cells to TNF-alpha cytotoxicity.
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收藏
页码:4027 / 4034
页数:8
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