The activation of p38 and apoptosis by the inhibition of ERK is antagonized by the phosphoinositide S-kinase/Akt pathway
The activation of p38 and apoptosis by the inhibition of ERK is antagonized by the phosphoinositide S-kinase/Akt pathway
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DOI：
10.1074/jbc.273.17.10792
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发表时间：
1998-04-24
影响因子：
4.8
通讯作者：
Moscat, J
中科院分区：
文献类型：
--
作者：
Berra, E;Diaz-Meco, MT;Moscat, J
最近，不同激酶级联在细胞凋亡控制中所起的作用受到了极大的关注。在许多经历程序性细胞死亡的细胞系统中观察到，应激激活激酶的触发伴随着细胞外信号调节激酶（ERK）途径的抑制。此外，磷酸肌醇 3-激酶 (PI 3-激酶)-Akt 信号级联的激活已被证明可以防止细胞凋亡。在这里，我们探讨了抑制 ERK 在应激激酶激活中所发挥的潜在作用，以及与 HeLa 细胞中 PI 3 激酶通路可能的串扰。我们发现，简单抑制 ERK 基础活性就足以触发细胞凋亡和 p38 激活，而 Jun N 末端激酶/应激激活蛋白激酶没有变化。这是一个依赖于半胱天冬酶的过程，并且被血清完全消除。与渥曼青霉素孵育或转染 p85 或 Akt 显性失活突变体可阻断血清的抑制功能，表明 PI 3-激酶-Akt 系统参与其中。与此一致，PI 3 激酶和 Akt 活性突变体的表达抑制 p38 激活和细胞凋亡。我们还在此表明，ERK 的抑制会触发半胱天冬酶系统，该系统以渥曼青霉素依赖性方式被血清消除。总的来说，这些结果证明了 ERK 和 p38 凋亡途径之间的联系，该途径受存活 PI 3-激酶-Akt 模块的调节，作用于 caspase 系统的上游。
Considerable attention has recently been focused on the role played by different kinase cascades in the control of apoptosis, The triggering of stress-activated kinases concomitant with the inhibition of the extracellular signal-regulated kinase (ERK) pathway has been observed in a number of cell systems undergoing programmed cell death. In addition, the activation of the phosphoinositide 3-kinase (PI 3-kinase)-Akt signaling cascade has been shown to protect from apoptosis. Here we have explored the potential role played by the inhibition of ERK in the activation of the stress kinases as well as the possible cross-talk with the PI 3-kinase pathway in HeLa cells. We show that the simple inhibition of ERK basal activity is sufficient to trigger apoptosis and p38 activation with no changes in Jun N-terminal kinase/stress-activated protein kinase. This is a process dependent on the caspases and is completely abrogated by serum. The incubation with wortmannin or the transfection of dominant negative mutants of p85 or Akt block the inhibitory function of serum, suggesting the involvement of the PI 3-kinase-Akt system. Consistent with this, expression of active mutants of PI 3-kinase and Akt inhibits p38 activation and apoptosis. We also show here that the inhibition of ERK triggers the caspase system, which is abolished by serum in a wortmannin-dependent manner. Collectively, these results demonstrate a link between ERK and the p38 apoptotic pathway that is modulated by the survival PI 3-kinase-Akt module, acting upstream the caspase system.