Cbl negatively regulates JNK activation and cell death.
Cbl negatively regulates JNK activation and cell death.
复制标题
Cbl 负向调节 JNK 激活和细胞死亡。
作者：
在此，我们探究了Cbl蛋白在神经元凋亡调控中的作用。在两种神经元凋亡范例——神经生长因子（NGF）剥夺和DNA损伤中，c - Cbl和Cbl - b的细胞水平在死亡发生之前就大幅下降。NGF剥夺还导致c - Cbl的酪氨酸磷酸化（很可能是其活化）迅速丧失。用小干扰RNA（siRNAs）靶向c - Cbl和Cbl - b以模拟它们的缺失/失活，会使神经元细胞对NGF剥夺或DNA损伤所促进的死亡更加敏感。Cbl蛋白可能影响神经元死亡的一种潜在机制是通过对凋亡的JNK信号通路的调控。我们证明Cbl蛋白与JNK通路组分MLK3和POSH相互作用，并且Cbl蛋白的敲低足以增加JNK通路活性。此外，c - Cbl的表达阻断了MLK向导致JNK活化的激酶级联下游组分传递信号的能力，并保护神经元细胞免受MLK诱导的死亡，但不能免受下游JNK激活剂的影响。基于这些发现，我们提出Cbl蛋白至少在一定程度上通过抑制MLK激活JNK信号通路的能力来抑制健康神经元中的细胞死亡。凋亡刺激导致Cbl蛋白/活性丧失，从而消除了对JNK活化和细胞死亡的关键抑制。
Here, we explore the role of Cbl proteins in regulation of neuronal apoptosis. In two paradigms of neuron apoptosis – nerve growth factor (NGF) deprivation and DNA damage – cellular levels of c-Cbl and Cbl-b fell well before onset of death. NGF deprivation also induced rapid loss of tyrosine phosphorylation (and most likely, activation) of c-Cbl. Targeting c-Cbl and Cbl-b with siRNAs to mimic their loss/inactivation sensitized neuronal cells to death promoted by NGF deprivation or DNA damage. One potential mechanism by which Cbl proteins might affect neuron death is by regulation of apoptotic JNK signaling. We demonstrate that Cbl proteins interact with the JNK pathway components MLK3 and POSH and that knockdown of Cbl proteins is sufficient to increase JNK pathway activity. Furthermore, expression of c-Cbl blocks the ability of MLKs to signal to downstream components of the kinase cascade leading to JNK activation and protects neuronal cells from death induced by MLKs, but not from downstream JNK activators. On the basis of these findings, we propose that Cbls suppress cell death in healthy neurons at least in part by inhibiting the ability of MLKs to activate JNK signaling. Apoptotic stimuli lead to loss of Cbl protein/activity, thereby removing a critical brake on JNK activation and on cell death.
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影响因子：
4
作者：
Kaabeche, K;Guenou, H;Marie, PJ
通讯作者：
Marie, PJ
影响因子：
4.8
作者：
Ettenberg, SA;Magnifico, A;Lipkowitz, S
通讯作者：
Lipkowitz, S
影响因子：
5.3
作者：
Mota, M;Reeder, M;Bazenet, CE
通讯作者：
Bazenet, CE
影响因子：
12.4
作者：
Denis, G;Mandard, S;Régnier, D
通讯作者：
Régnier, D
DOI：
10.1083/jcb.123.5.1207
发表时间：
1993-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Deckwerth TL;Johnson EM Jr
通讯作者：
Johnson EM Jr