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首页> 外文期刊>Molecular and Cellular Biology >Tumor Promoter Arsenite Activates Extracellular Signal-Regulated Kinase through a Signaling Pathway Mediated by Epidermal Growth Factor Receptor and Shc
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Tumor Promoter Arsenite Activates Extracellular Signal-Regulated Kinase through a Signaling Pathway Mediated by Epidermal Growth Factor Receptor and Shc

机译：肿瘤启动子亚砷酸盐通过表皮生长因子受体和Shc介导的信号通路激活细胞外信号调节激酶。

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Although arsenite is an established carcinogen, the mechanisms underlying its tumor-promoting properties are poorly understood. Previously, we reported that arsenite treatment leads to the activation of the extracellular signal-regulated kinase (ERK) in rat PC12 cells through a Ras-dependent pathway. To identify potential mediators of the upstream signaling cascade, we examined the tyrosine phosphorylation profile in cells exposed to arsenite. Arsenite treatment rapidly stimulated tyrosine phosphorylation of several proteins in a Ras-independent manner, with a pattern similar to that seen in response to epidermal growth factor (EGF) treatment. Among these phosphorylated proteins were three isoforms of the proto-oncoprotein Shc as well as the EGF receptor (EGFR). Tyrosine phosphorylation of Shc allowed for enhanced interactions between Shc and Grb2 as identified by coimmunoprecipitation experiments. The arsenite-induced tyrosine phosphorylation of Shc, enhancement of Shc and Grb2 interactions, and activation of ERK were all drastically reduced by treatment of cells with either the general growth factor receptor poison suramin or the EGFR-selective inhibitor tyrphostin AG1478. Down-regulation of EGFR expression through pretreatment of cells with EGF also attenuated ERK activation and Shc tyrosine phosphorylation in response to arsenite treatment. These results demonstrate that the EGFR and Shc are critical mediators in the activation of the Ras/ERK signaling cascade by arsenite and suggest that arsenite acts as a tumor promoter largely by usurping this growth factor signaling pathway.
机译：尽管亚砷酸盐是一种公认​​的致癌物，但其促肿瘤性质的机制尚不清楚。以前，我们报道过亚砷酸盐治疗通过Ras依赖性途径导致大鼠PC12细胞中细胞外信号调节激酶（ERK）的激活。为了确定上游信号级联的潜在介体，我们检查了暴露于亚砷酸盐的细胞中的酪氨酸磷酸化谱。亚砷酸盐处理以Ras独立的方式迅速刺激了几种蛋白质的酪氨酸磷酸化，其模式类似于对表皮生长因子（EGF）处理所见。在这些磷酸化蛋白中，原癌蛋白Shc和EGF受体（EGFR）的三种同工型。如通过共免疫沉淀实验所鉴定，Shc的酪氨酸磷酸化可增强Shc与Grb2之间的相互作用。通过用普通生长因子受体毒物苏拉明或EGFR选择性抑制剂酪氨酸蛋白酶抑制剂AG1478处理细胞，可大大减少砷诱导的Shc酪氨酸磷酸化，Shc和Grb2相互作用的增强以及ERK的激活。通过对细胞进行EGF预处理，EGFR表达的下调也减弱了ERK活化和Shc酪氨酸磷酸化，这是对亚砷酸盐处理的反应。这些结果表明，EGFR和Shc是亚砷酸盐激活Ras / ERK信号级联反应的关键介体，并表明亚砷酸盐主要通过篡改该生长因子信号通路来充当肿瘤启动子。

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