NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells:: a mechanism for the anti-apoptotic effect of NF-κB
NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells:: a mechanism for the anti-apoptotic effect of NF-κB
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DOI：
10.1038/sj.onc.1204570
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发表时间：
2001-07-19
期刊：
影响因子：
8
通讯作者：
Besançon, F
中科院分区：
文献类型：
--
作者：
Javelaud, D;Besançon, F
我们最近报道，抑制NF-κ B活化是I κ-B α [I κ B α（A32/36）]的抗降解形式过度表达的结果，它使尤文肉瘤细胞对TNF α诱导的杀伤敏感。c-Jun N-末端激酶（JNK）已被证明参与由某些刺激触发的死亡信号传导，并被TNF激活。为了深入了解NF-κ B抗凋亡作用的机制，我们比较了对照细胞和NF-κ B激活受损细胞中TNF α激活JNK的情况。我们发现JNK激活在对照细胞中是短暂的，但在I κ-B α（A32/36）表达细胞中仍然升高。NF-κ B特异性抑制JNK途径，因为在两种细胞中其他TNF α激活的MAP激酶p38的激活动力学是相同的。在表达I κ B α（A32/36）的细胞中JNK激活的延长不受广谱半胱天冬酶抑制剂Z-VAD-FMK的抑制，因此不是半胱天冬酶激活的结果，用磷酸酶抑制剂钒酸盐预处理对照细胞大大延长了TNF α对JNK的激活，并导致这种细胞因子诱导细胞凋亡。此外，JNK 1的显性负性突变体的过表达降低了表达NF-κ B的超级阻遏物的细胞中TNF α诱导的凋亡，表明JNK 1的持续激活参与了TNF α触发的死亡信号传导。我们的结果提供了证据，即NF-κ B对JNK激活的阻遏参与了TNF α处理的尤文肉瘤细胞中该转录因子的抗凋亡作用。
We recently reported that inhibition of NF-kappaB activation as a consequence of the overexpression of a degradation-resistant form of I kappa -B alpha [I kappaB alpha (A32/36)] sensitized Ewing sarcoma cells to TNF alpha -induced killing. The c-Jun N-terminal kinases (JNK) have been shown to participate in death signaling triggered by certain stimuli and are activated by TNF. To obtain insight into the mechanism of the anti-apoptotic effect of NF-kappaB, we compared the profiles of JNK activation by TNF alpha in control cells and in cells in which NF-kappaB activation was impaired. We show here that JNK activation was transient in control cells but remained elevated in I kappa -B alpha (A32/36)-expressing cells. NF-kappaB repressed specifically the JNK pathway, since the kinetics of activation of the other TNF alpha -activated-MAP kinase p38 were identical in both cells, Prolongation of JNK activation in I kappaB alpha (A32/36)-expressing cells was not inhibited by the broad spectrum caspase inhibitor Z-VAD-FMK and thus was not the consequence of caspase activation, Pretreatment of control cells with the phosphatase inhibitor vanadate greatly prolonged JNK activation by TNF alpha and resulted in induction of apoptosis by this cytokine. Moreover, overexpression of a dominant-negative mutant of JNK1 decreased TNF alpha -induced apoptosis in cells expressing the super repressor of NF-kappaB, indicating that the sustained activation of JNK1 participated in death signaling triggered by TNF alpha, Our results provide evidence that the repression of JNK activation by NF-kappaB participates in the anti-apoptotic effect of this transcription factor in TNF alpha -treated Ewing sarcoma cells.