Activation of the Stat3 signaling pathway is required for differentiation by interleukin-6 in PC12-E2 cells

作     者：Wu, YY Bradshaw, RA 

作者机构：Univ Calif Irvine Coll Med Dept Anat & Neurobiol Irvine CA 92697 USA Univ Calif Irvine Coll Med Dept Physiol & Biophys Irvine CA 92697 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2000年第275卷第3期

页      面：2147-2156页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NIA NIH HHS [AG09735] Funding Source: Medline 

主　　题：衔接蛋白质类 信号转导 衔接蛋白质类 膜泡运输 细胞分化/生理学 细胞系 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢 剂量效应关系 药物 酶抑制剂/药理学 类黄酮物质/药理学 基因表达调控 基因 显性 干扰素γ/代谢 白细胞介素6/代谢 诱变 定点 神经生长因子类/遗传学 神经生长因子类/代谢 神经突/代谢 PC12细胞 磷酰化 蛋白质类/遗传学 蛋白质类/代谢 原癌基因蛋白质p21(ras)/遗传学 原癌基因蛋白质p21(ras)/代谢 STAT1转录因子 STAT3转录因子 丝氨酸/代谢 Shc信号衔接蛋白质类 信号传导 时间因素 反式激活因子类/遗传学 反式激活因子类/代谢 酪氨酸/代谢 动物 人类 大鼠 

摘      要：The role of signal transducer and activator of transcription (STAT) signaling pathways in the interleukin-6 (IL-6)-induced morphological differentiation of PC12-E2 cells was assessed using wild type and dominant negative mutants of Stat1 and Stat3, containing Tyr -- Phe (YF), Ser -- Ala (SA), and the double mutations (DM), respectively. FS3-YF or FS3-DM markedly inhibited the IL-6-induced response, but overexpression of FS3-SA caused only a modest inhibition. Expression of all Stat3 mutants had no effect on NGF-induced neurite outgrowth. Overexpression of wild type Stat1 protein inhibited IL-6 activated DNA binding complexes containing Stat3 homodimers, which may explain the partial negative effect of Stat1 on IL-6-induced neurite outgrowth. Specificity of these STAT constructs was confirmed using luciferase reporter gene assays, which showed that IL-6-activated transcription was blocked by expression of FS3-YF and FS3-DM and that FS1 enhanced the interferon gamma-activated transcription. Thus, in PC12-E2 cells, Stat3 homodimers are preferentially activated by IL-6, indicating a role for Stat3 in the regulation of cellular differentiation. Furthermore, IL-6 induced robust neurite outgrowth in PC12-E2 cells expressing dominant negative forms of RAS or SHC or in cells pretreated with the mitogen-activated protein kinase mitogen-activated protein kinase kinase inhibitor, PD98059, Thus, activation of the Stat3 signaling pathway, but not RAS/ERK dependent pathways, is essential for differentiation of PC12-E2 cells by IL-6.