Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3β in SH-SY5Y neuroblastoma cells
Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3β in SH-SY5Y neuroblastoma cells
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DOI：
10.1111/j.1471-4159.2004.02948.x
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发表时间：
2005-03-01
影响因子：
4.7
通讯作者：
Pei, JJ
中科院分区：
文献类型：
--
作者：
An, WL;Bjorkdahl, C;Pei, JJ
我们之前报道过阿尔茨海默病（AD）中带有神经原纤维缠结（NFT）的神经元中活化蛋白激酶B（PKB）、糖原合酶激酶（GSK）-3β、细胞外信号调节激酶（ERK1/2）、c-Jun N末端激酶（JNK）、p38和p70 S6激酶（p70S6K）的异常积累。然而，这些 tau 候选激酶参与 p70S6K 和 GSK-3beta 磷酸化调节的机制尚不清楚。在本研究中，使用100 muM硫酸锌，并在血清剥夺的SH-SY5Y神经母细胞瘤细胞中研究了磷脂酰肌醇3激酶（PI3K）和丝裂原激活蛋白激酶（MAPK）途径的各种成分对p70S6K和GSK-3beta磷酸化的影响。我们发现锌可以诱导磷酸化 (p) p70S6K、p-PKB、p-GSK-3beta、p-ERK1/2、p-JNK 和 p-p38 的增加，特别是在长期治疗（4-8 小时）中。用不同抑制剂（包括雷帕霉素、渥曼青霉素、LY294002 和 U0126 及其组合）治疗表明，p70S6K 和 GSK-3beta 的磷酸化受到雷帕霉素依赖性、PI3K 和 MAPK 途径的调节。此外，p70S6K 和 GSK-3beta 的磷酸化影响 Tau-1 位点未磷酸化和 PHF-1 位点磷酸化的 tau 水平，p70S6K 磷酸化影响总 tau 水平。因此，100 muM 锌可能会激活 PKB、GSK-3beta、ERK1/2、JNK、p38 和 p70S6K，从而参与 SH-SY5Y 细胞中 tau 蛋白的变化。
We have previously reported an aberrant accumulation of activated protein kinase B (PKB), glycogen synthase kinase (GSK)-3beta, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and p70 S6 kinase (p70S6K) in neurons bearing neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). However, the mechanism by which these tau candidate kinases are involved in the regulation of p70S6K and GSK-3beta phosphorylation is unknown. In the current study, 100 muM zinc sulfate was used, and influences of various components of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on p70S6K and GSK-3beta phosphorylation have been investigated in serum-deprived SH-SY5Y neuroblastoma cells. We found that zinc could induce an increase of phosphorylated (p) p70S6K, p-PKB, p-GSK-3beta, p-ERK1/2, p-JNK and p-p38, especially in long-term treatment (4-8 h). Treatment with different inhibitors including rapamycin, wortmannin, LY294002, and U0126, and their combinations, indicated that phosphorylation of p70S6K and GSK-3beta is regulated by rapamycin-dependent, PI3K and MAPK pathways. Furthermore, phosphorylation of p70S6K and GSK-3beta affected levels of tau unphosphorylated at the Tau-1 site and phosphorylated at the PHF-1 site, and p70S6K phosphorylation affected the total tau level. Thus, 100 muM zinc might activate PKB, GSK-3beta, ERK1/2, JNK, p38 and p70S6K, that are consequently involved in tau changes in SH-SY5Y cells.