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首页> 外文期刊>Cellular Signalling >MKK7γ1 reverses nerve growth factor signals: Proliferation and cell death instead of neuritogenesis and protection
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MKK7γ1 reverses nerve growth factor signals: Proliferation and cell death instead of neuritogenesis and protection

机译：MKK7γ1逆转神经生长因子信号：增殖和细胞死亡，而不是神经发生和保护

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摘要

c-Jun N-terminal kinases (JNKs) are the exclusive downstream substrates of mitogen-activated protein kinase kinase 7 (MKK7). Recently, we have shown that a single MKK7 splice variant, MKK7γ1, substantially changes the functions of JNKs in na?ve PC12 cells. Here we provide evidence that MKK7γ1 blocks NGF-mediated differentiation and sustains proliferation by interfering with the NGF-triggered differentiation programme at several levels: (i) down-regulation of the NGF receptors TrkA and p75; (ii) attenuation of the differentiation-promoting pathways ERK1/2 and AKT; (iii) increase of JNK1 and JNK2, especially the JNK2 54kDa splice variants; (iv) repression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which normally supports NGF-mediated cell cycle arrest; (v) strong induction of the cell cycle promoter CyclinD1, and (vi) profound changes of p53 functions. Moreover, MKK7γ1 substantially changes the responsiveness to stress. Whereas NGF differentiation protects PC12 cells against taxol-induced apoptosis, MKK7γ1 triggers an escape from cell cycle arrest and renders transfected cells sensitive to taxol-induced death. This stress response completely differs from na?ve PC12 cells, where MKK7γ1 protects against taxol-induced cell death. These novel aspects on the regulation of JNK signalling emphasise the importance of MKK7γ1 in its ability to reverse basic cellular programmes by simply using JNKs as effectors. Furthermore, our results highlight the necessity for the cells to balance the expression of JNK activators to ensure precise intracellular processes.
机译：c-Jun N末端激酶（JNK）是促分裂原活化蛋白激酶7（MKK7）的排他性下游底物。最近，我们显示了单个MKK7剪接变体MKK7γ1实质上改变了天然PC12细胞中JNK的功能。在这里，我们提供证据表明MKK7γ1在几个水平上干扰NGF触发的分化程序，从而阻断NGF介导的分化并维持增殖：（i）下调NGF受体TrkA和p75; （ii）减弱促分化途径ERK1 / 2和AKT; （iii）JNK1和JNK2，特别是JNK2 54kDa剪接变体的增加; （iv）抑制通常依赖NGF介导的细胞周期阻滞的细胞周期蛋白依赖性激酶抑制剂p21WAF1 / CIP1; （v）强烈诱导细胞周期启动子CyclinD1，以及（vi）p53功能的深刻变化。而且，MKK7γ1实质上改变了对压力的响应性。 NGF的分化可以保护PC12细胞免受紫杉醇诱导的细胞凋亡，而MKK7γ1触发了细胞周期阻滞的逃逸，并使转染的细胞对紫杉醇诱导的死亡敏感。这种应激反应与幼稚的PC12细胞完全不同，后者的MKK7γ1可以防止紫杉醇诱导的细胞死亡。这些关于JNK信号调控的新颖方面强调了MKK7γ1在通过简单地使用JNK作为效应子来逆转基本细胞程序的能力中的重要性。此外，我们的结果突出了细胞平衡JNK激活剂表达以确保精确的细胞内过程的必要性。

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