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首页> 外文期刊>Molecular and Cellular Biology >Apoptosis Suppression by Raf-1 and MEK1 Requires MEK- and Phosphatidylinositol 3-Kinase-Dependent Signals
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Apoptosis Suppression by Raf-1 and MEK1 Requires MEK- and Phosphatidylinositol 3-Kinase-Dependent Signals

机译：Raf-1和MEK1抑制细胞凋亡需要MEK和磷脂酰肌醇3-激酶依赖信号。

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Two Ras effector pathways leading to the activation of Raf-1 and phosphatidylinositol 3-kinase (PI3K) have been implicated in the survival signaling by the interleukin 3 (IL-3) receptor. Analysis of apoptosis suppression by Raf-1 demonstrated the requirement for mitochondrial translocation of the kinase in this process. This could be achieved either by overexpression of the antiapoptotic protein Bcl-2 or by targeting Raf-1 to the mitochondria via fusion to the mitochondrial protein Mas p70. Mitochondrially active Raf-1 is unable to activate extracellular signal-related kinase 1 (ERK1) and ERK2 but suppresses cell death by inactivating the proapoptotic Bcl-2 family member BAD. However, genetic and biochemical data also have suggested a role for the Raf-1 effector module MEK-ERK in apoptosis suppression. We thus tested for MEK requirement in cell survival signaling using the interleukin 3 (IL-3)-dependent cell line 32D. MEK is essential for survival and growth in the presence of IL-3. Upon growth factor withdrawal the expression of constitutively active MEK1 mutants significantly delays the onset of apoptosis, whereas the presence of a dominant negative mutant accelerates cell death. Survival signaling by MEK most likely results from the activation of ERKs since expression of a constitutively active form of ERK2 was as effective in protecting NIH 3T3 fibroblasts against doxorubicin-induced cell death as oncogenic MEK. The survival effect of activated MEK in 32D cells is achieved by both MEK- and PI3K-dependent mechanisms and results in the activation of PI3K and in the phosphorylation of AKT. MEK and PI3K dependence is also observed in 32D cells protected from apoptosis by oncogenic Raf-1. Additionally, we also could extend these findings to the IL-3-dependent pro-B-cell line BaF3, suggesting that recruitment of MEK is a common mechanism for survival signaling by activated Raf. Requirement for the PI3K effector AKT in this process is further demonstrated by the inhibitory effect of a dominant negative AKT mutant on Raf-1-induced cell survival. Moreover, a constitutively active form of AKT synergizes with Raf-1 in apoptosis suppression. In summary these data strongly suggest a Raf effector pathway for cell survival that is mediated by MEK and AKT.
机译：导致Raf-1和磷脂酰肌醇3激酶（PI3K）激活的两种Ras效应子途径已由白介素3（IL-3）受体参与了生存信号传递。 Raf-1对细胞凋亡抑制的分析表明，在此过程中需要激酶的线粒体易位。这可以通过抗凋亡蛋白Bcl-2的过表达或通过与线粒体蛋白Mas p70融合将Raf-1靶向线粒体来实现。线粒体活性Raf-1无法激活细胞外信号相关激酶1（ERK1）和ERK2，但通过失活促凋亡Bcl-2家族成员BAD抑制细胞死亡。然而，遗传和生化数据也提示Raf-1效应模块MEK-ERK在细胞凋亡抑制中的作用。因此，我们使用白介素3（IL-3）依赖性细胞系32D测试了细胞存活信号转导中的MEK需求。在IL-3存在下，MEK对于存活和生长至关重要。退出生长因子后，组成型活性MEK1突变体的表达显着延迟了细胞凋亡的发生，而显性负突变体的存在则加速了细胞死亡。 MEK的生存信号很可能来自ERK的活化，因为ERK2的组成型活性形式的表达与致癌性MEK一样有效地保护了NIH 3T3成纤维细胞免受阿霉素诱导的细胞死亡。活化的MEK在32D细胞中的存活效应是通过依赖于MEK和PI3K的机制实现的，并导致PI3K的活化和AKT的磷酸化。在由致癌Raf-1保护免于凋亡的32D细胞中也观察到MEK和PI3K依赖性。此外，我们还可以将这些发现扩展至依赖IL-3的pro-B细胞系BaF3，这表明MEK的募集是激活Raf进行生存信号转导的常见机制。 PI3K效应子AKT在此过程中的需求通过显性负性AKT突变体对Raf-1诱导的细胞存活的抑制作用进一步证明。此外，AKT的组成型活性形式与Raf-1协同抑制细胞凋亡。总之，这些数据强烈暗示了由MEK和AKT介导的Raf效应子途径的细胞存活。

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