N-cadherin mediates neuronal cell survival through Bim down-regulation.
N-cadherin mediates neuronal cell survival through Bim down-regulation.
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DOI：
10.1371/journal.pone.0033206
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Birbes H
中科院分区：
文献类型：
--
作者：
Lelièvre EC;Plestant C;Boscher C;Wolff E;Mège RM;Birbes H
N-钙粘蛋白是一种主要的粘附分子，参与神经系统的发育和可塑性。 N-钙粘蛋白介导的细胞粘附调节神经上皮细胞极性、神经元前体迁移、生长锥迁移和突触可塑性。在体外，它参与信号事件调节细胞迁移、增殖和分化等过程。 N-钙粘蛋白还与非神经元细胞中针对细胞凋亡的粘附依赖性保护有关。在这项研究中，我们研究了 N-钙粘蛋白的参与是否参与神经元细胞生存/死亡平衡的控制。我们观察到，与聚-L-赖氨酸上的非特异性粘附相比，将原代小鼠脊髓神经元或原代大鼠海马神经元接种在 N-钙粘蛋白重组基质上可大大提高其存活率。我们发现，在没有其他生存因子（细胞-基质相互作用和血清）的情况下，N-钙粘蛋白的参与可以保护 GT1-7 神经元细胞免于凋亡。然后，我们利用该细胞系寻找与 N-钙粘蛋白结合的生存效应相关的信号通路。 PI3 激酶/Akt 存活途径及其下游效应子 Bad 不参与其中，因为没有观察到 Akt 或 Bad 蛋白响应 N-钙粘蛋白接合而发生磷酸化。相反，N-钙粘蛋白的参与激活了 Erk1/2 MAP 激酶通路。此外，N-钙粘蛋白连接介导促凋亡蛋白 Bim-EL 的水平降低 2 倍，而抗凋亡蛋白 Bcl-2 的水平没有变化。用 U0126 抑制 Mek1/2 激酶，以及由此产生的 Erk1/2 磷酸化抑制，诱导 Bim-EL 水平增加和接种在 N-钙粘蛋白底物上的细胞凋亡，表明 Erk 磷酸化对于细胞生存是必需的。最后，Bim-EL 磷酸化缺陷形式的过度表达阻止了 N-钙粘蛋白接合诱导的细胞存活。总之，我们的结果表明，N-钙粘蛋白结合通过增强 MAP 激酶途径和下调促凋亡蛋白 Bim-EL 介导神经元细胞存活。
N-cadherin is a major adhesion molecule involved in the development and plasticity of the nervous system. N-cadherin-mediated cell adhesion regulates neuroepithelial cell polarity, neuronal precursor migration, growth cone migration and synaptic plasticity. In vitro, it has been involved in signaling events regulating processes such as cell mobility, proliferation and differentiation. N-cadherin has also been implicated in adhesion-dependent protection against apoptosis in non-neuronal cells. In this study, we investigated if the engagement of N-cadherin participates to the control of neuronal cells survival/death balance. We observed that plating either primary mouse spinal cord neurons or primary rat hippocampal neurons on N-cadherin recombinant substrate greatly enhances their survival compared to non-specific adhesion on poly-L-lysine. We show that N-cadherin engagement, in the absence of other survival factors (cell-matrix interactions and serum), protects GT1-7 neuronal cells against apoptosis. Using this cell line, we then searched for the signaling pathways involved in the survival effect of N-cadherin engagement. The PI3-kinase/Akt survival pathway and its downstream effector Bad are not involved, as no phosphorylation of Akt or Bad proteins in response to N-cadherin engagement was observed. In contrast, N-cadherin engagement activated the Erk1/2 MAP kinase pathway. Moreover, N-cadherin ligation mediated a 2-fold decrease in the level of the pro-apoptotic protein Bim-EL whereas the level of the anti-apoptotic protein Bcl-2 was unchanged. Inhibition of Mek1/2 kinases with U0126, and the resulting inhibition of Erk1/2 phosphorylation, induced the increase of both the level of Bim-EL and apoptosis of cells seeded on the N-cadherin substrate, suggesting that Erk phosphorylation is necessary for cell survival. Finally, the overexpression of a phosphorylation defective form of Bim-EL prevented N-cadherin-engagement induced cell survival. In conclusion, our results show that N-cadherin engagement mediates neuronal cell survival by enhancing the MAP kinase pathway and down-regulating the pro-apoptotic protein Bim-EL.
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DOI：
10.1152/ajprenal.2000.278.5.f758
发表时间：
2000-05-01
影响因子：
4.2
作者：
Bergin, E;Levine, JS;Lieberthal, W
通讯作者：
Lieberthal, W
影响因子：
4.8
作者：
Boscher, Cecile;Mege, Rene-Marc
通讯作者：
Mege, Rene-Marc
DOI：
10.1083/jcb.129.2.489
发表时间：
1995-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hermiston ML;Gordon JI
通讯作者：
Gordon JI
DOI：
10.1083/jcb.107.4.1575
发表时间：
1988-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gumbiner B;Stevenson B;Grimaldi A
通讯作者：
Grimaldi A
DOI：
10.1161/01.atv.0000163183.27658.4b
发表时间：
2005-05-01
影响因子：
8.7
作者：
Koutsouki, E;Beeching, CA;George, SJ
通讯作者：
George, SJ