Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death.
Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death.
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DOI：
10.1124/mol.108.049064
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发表时间：
2008-10
影响因子：
3.6
通讯作者：
DeFranco DB
中科院分区：
文献类型：
--
作者：
Ho Y;Samarasinghe R;Knoch ME;Lewis M;Aizenman E;DeFranco DB
小鼠HT22神经母细胞瘤细胞系和胚胎大鼠未成熟皮质神经元中谷胱甘肽耗竭诱导的氧化应激导致细胞外信号调节激酶-1/2(ERK1/2)的延迟、持续激活，这是细胞死亡所必需的。ERK1/2的这种持续激活主要是通过选择性地抑制不同的ERK1/2导向的磷酸酶来实现的，要么是通过增强降解(即丝裂原激活的蛋白激酶[MAPK]磷酸酶-1)，要么是通过降低酶活性(即对于蛋白磷酸酶2A型[PP-2A])。氧化应激导致HT22细胞和谷胱甘肽耗竭的未成熟神经元中ERK1/2磷酸酶活性的抑制，因为抗氧化剂丁基羟基苯甲醚(BHA)处理的细胞中的磷酸酶活性恢复。这会降低ERK1/2的激活和神经保护作用。此外，在谷胱甘肽诱导的HT22细胞和未成熟神经元中，伴随着氧化应激而产生的细胞内游离锌的增加有助于选择性地抑制ERK1/2磷酸酶活性和细胞死亡。最后，ERK1/2也起到维持高锌水平的作用。因此，氧化应激下神经元内锌的升高可以通过激活的ERK1/2触发一个强大的正反馈环路，迅速启动依赖锌的细胞死亡途径。
Oxidative stress induced by glutathione depletion in the mouse HT22 neuroblastoma cell line and embryonic rat immature cortical neurons causes a delayed, sustained activation of extracellular signal-regulated kinases-1/2 (ERK1/2), which is required for cell death. This sustained activation of ERK1/2 is mediated primarily by a selective inhibition of distinct ERK1/2-directed phosphatases either by enhanced degradation (i.e. for Mitogen activated protein kinase [MAPK] Phosphatase-1) or as shown here by reductions in enzymatic activity (i.e. for Protein Phosphatase type 2A [PP-2A]). The inhibition of ERK1/2 phosphatases in HT22 cells and immature neurons subjected to glutathione depletion results from oxidative stress as phosphatase activity is restored in cells treated with the antioxidant butylated hydroxyanisole (BHA). This leads to reduced ERK1/2 activation and neuroprotection. Furthermore, an increase in free intracellular zinc that accompanies glutathione-induced oxidative stress in HT22 cells and immature neurons contributes to selective inhibition of ERK1/2 phosphatase activity and cell death. Finally, ERK1/2 also functions to maintain elevated levels of zinc. Thus the elevation of intracellular zinc within neurons subjected to oxidative stress can trigger a robust positive feedback loop operating through activated ERK1/2 that rapidly sets into motion a zinc-dependent pathway of cell death.
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影响因子：
4
作者：
Devinney, MJ;Reynolds, IJ;Dineley, KE
通讯作者：
Dineley, KE
DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
DOI：
10.1073/pnas.96.5.1936
发表时间：
1999-03-02
影响因子：
11.1
作者：
Maret, W;Jacob, C;Fischer, EH
通讯作者：
Fischer, EH
影响因子：
4.7
作者：
Aizenman, E;Stout, AK;Reynolds, IJ
通讯作者：
Reynolds, IJ
影响因子：
3
作者：
Hara, H;Aizenman, E
通讯作者：
Aizenman, E