Extracellular zinc activates p70 S6 kinase through the phosphatidylinositol 3-kinase signaling pathway
Extracellular zinc activates p70 S6 kinase through the phosphatidylinositol 3-kinase signaling pathway
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DOI：
10.1074/jbc.m001975200
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发表时间：
2000-08-25
影响因子：
4.8
通讯作者：
Chung, J
中科院分区：
文献类型：
--
作者：
Kim, S;Jung, Y;Chung, J
我们学习了一个可能的角色激活的细胞外锌离子p70S6k,扮演着一个重要的角色在细胞的发展从G (1) S期的细胞周期,瑞士3 t3细胞的治疗与硫酸锌的激活和磷酸化导致p70S6k剂量依赖性的方式,激活的p70S6k锌治疗是两相的,30分钟后的早期阶段后期阶段在120分钟。12-肉豆蔻酸13-醋酸磷对PKC （phorbol 12-肉豆蔻酸13-醋酸磷）的下调可以部分抑制锌诱导的p70S6k活化，但不显著。此外，特异性钙依赖性PKC抑制剂Go6976没有显著抑制锌对p70S6k的激活。这些结果表明，锌诱导p70S6k的活化与PKC无关，细胞外钙也不参与锌对p70S6k的活化。利用p70S6k信号通路的特异性抑制剂，即雷帕霉素、wortmannin和LY294002进一步表征锌诱导的p70S6k活化，发现锌在mTOR/FRAP/RAFT和磷脂酰肌醇3-激酶（PI3K）的上游起作用，因为这些抑制剂会抑制锌诱导的p70S6k活性。此外，p70S6k的上游组分Akt和p70S6k一样，被锌双相激活。Akt和PDK1的显性干扰等位基因阻断了锌诱导的p70S6k的激活，而PI3K的脂质激酶活性则被锌有效激活。综上所述，我们的数据表明锌通过PI3K信号通路激活p70S6k。
We have studied a possible role of extracellular zinc ion in the activation of p70S6k, which plays an important role in the progression of cells from the G(1) to S phase of the cell cycle, Treatment of Swiss 3T3 cells with zinc sulfate led to the activation and phosphorylation of p70S6k in a dose-dependent manner, The activation of p70S6k by zinc treatment was biphasic, the early phase being at 30 min followed by the late phase at 120 min. The zinc-induced activation of p70S6k was partially inhibited by down-regulation of phorbol 12-myristate 13-acetate-responsive protein kinase C (PKC) by chronic treatment with phorbol 12-myristate 13-acetate, but this was not significant. Moreover, Go6976, a specific calcium-dependent PKC inhibitor, did not significantly inhibit the activation of p70S6k by zinc. These results demonstrate that the zinc-induced activation of p70S6k is not related to PKC, Also, extracellular calcium was not involved in the activation of p70S6k by zinc. Further characterization of the zinc-induced activation of p70S6k using specific inhibitors of the p70S6k signaling pathway, namely rapamycin, wortmannin, and LY294002, showed that zinc acted upstream of mTOR/FRAP/RAFT and phosphatidylinositol 3-kinase (PI3K), because these inhibitors caused the inhibition of zinc-induced p70S6k activity, In addition, Akt, the upstream component of p70S6k, was activated by zinc in a biphasic manner, as was p70S6k, Moreover, dominant interfering alleles of Akt and PDK1 blocked the zinc-induced activation of p70S6k, whereas the lipid kinase activity of PI3K was potently activated by zinc, Taken together, our data suggest that zinc activates p70S6k through the PI3K signaling pathway.