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首页> 外文期刊>Molecular and Cellular Biology >Cellular N-Ras Promotes Cell Survival by Downregulation of Jun N-Terminal Protein Kinase and p38
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Cellular N-Ras Promotes Cell Survival by Downregulation of Jun N-Terminal Protein Kinase and p38

机译：细胞N-Ras通过下调Jun N末端蛋白激酶和p38促进细胞存活

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Cellular N-Ras provides a steady-state antiapoptotic signal, at least partially through the regulation of phosphorylated Akt and Bad levels. Fibroblasts lacking c-N-Ras expression are highly sensitive to the induction of apoptosis by a variety of agents. Reduction of pBad and pAkt levels using a phosphatidylinositol 3-kinase inhibitor was not sufficient to sensitize the control cell population to the high level of apoptosis observed in the N-Ras knockout cell lines, suggesting that c-N-Ras provides at least one other antiapoptotic signal. Stimulation of the control cells with apoptotic agents results in a transient increase in Jun N-terminal protein kinase (JNK)/p38 activity that decreased to baseline levels during the time course of the experiments. In all cases, however, sustained JNK/p38 activity was observed in cells lacking c-N-Ras expression. This correlated with sustained levels of phosphorylated MKK4 and MKK3/6, upstream activators of JNK and p38, respectively. Mimicking the sustained activation of JNK in the control cells did result in increasing their sensitivity to apoptotic agents, suggesting that prolonged JNK activity is a proapoptotic event. We also examined the potential downstream c-N-Ras targets that might be involved in regulating the duration of the JNK/p38 signal. Only the RalGDS 37G-N-Ras protein protected the N-Ras knockout cells from apoptosis and restored transient rather than sustained JNK activation. These data suggest that cellular N-Ras provides an antiapoptotic signal through at least two distinct mechanisms, one which regulates steady-state pBad and pAkt levels and one which regulates the duration of JNK/p38 activity following an apoptotic challenge.
机译：细胞N-Ras至少部分地通过磷酸化Akt和Bad水平的调节来提供稳态抗凋亡信号。缺乏c-N-Ras表达的成纤维细胞对多种药物诱导的凋亡高度敏感。使用磷脂酰肌醇3-激酶抑制剂降低pBad和pAkt水平不足以使对照细胞群体对N-Ras基因敲除细胞系中观察到的高凋亡水平敏感，这表明cN-Ras提供了至少一种其他抗凋亡信号。用凋亡因子刺激对照细胞导致Jun N-末端蛋白激酶（JNK）/ p38活性的瞬时增加，在实验过程中下降到基线水平。然而，在所有情况下，在缺乏c-N-Ras表达的细胞中均观察到持续的JNK / p38活性。这分别与磷酸化的MKK4和MKK3 / 6（JNK和p38的上游激活剂）的持续水平相关。模仿对照细胞中JNK的持续活化，确实会导致其对凋亡因子的敏感性增加，这表明延长的JNK活性是促凋亡事件。我们还研究了可能参与调节JNK / p38信号持续时间的潜在下游c-N-Ras目标。只有RalGDS 37G-N-Ras蛋白保护N-Ras敲除细胞免于凋亡，并恢复了短暂的而不是持续的JNK活化。这些数据表明细胞N-Ras通过至少两种不同的机制提供抗凋亡信号，一种机制调节稳态的pBad和pAkt水平，另一种机制调节凋亡攻击后JNK / p38活性的持续时间。

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