c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic - Role in carcinogenesis
c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic - Role in carcinogenesis
复制标题
DOI：
10.1074/jbc.m109136200
复制
发表时间：
2002-01-25
影响因子：
4.8
通讯作者：
Luster, MI
中科院分区：
文献类型：
--
作者：
Simeonova, PP;Wang, SY;Luster, MI
在世界各地砷中毒流行地区，环境或职业暴露于砷与皮肤癌、膀胱癌和呼吸道癌的风险大大增加有关。砷通过影响负责细胞增殖的特定细胞信号转导途径而具有肿瘤促进剂的许多特性。表皮生长因子受体（EGFR）-细胞外信号调节蛋白激酶（ERK）途径的激活在介导与细胞生长调节相关的基因表达中是重要的。在目前的研究中，我们证明，砷激活EGFR和ERK在人尿路上皮细胞系。砷引起的EGFR磷酸化是配体非依赖性的，不涉及主要的自磷酸化位点Tyr（1173）。c-Src活性也可被砷诱导，并且是EGFR和ERK激活的先决条件。与这些体外观察结果一致，小鼠暴露于饮用水中的砷（先前已发现其与AP-1活化和上皮细胞增殖相关）诱导膀胱中的EGFR和ERK活化。这种反应还伴随着与EGFR相互作用的c-Src水平的增加。这些研究结果代表了一个潜在的途径介导砷诱导的表型变化的尿路上皮。
Environmental or occupational exposure to arsenic is associated with a greatly increased risk of skin, urinary bladder, and respiratory tract cancers in arseniasis-endemic areas throughout the world. Arsenic shares many properties of tumor promoters by affecting specific cell signal transduction pathways responsible for cell proliferation. The activation of the epidermal growth factor receptor (EGFR)-extracellular signal-regulated protein kinase (ERK) pathway is important in mediating gene expression related to regulation of cellular growth. In the current studies, we demonstrate that arsenic activates EGFR and ERK in a human uroepithelial cell line. The EGFR phosphorylation by arsenic is ligand-independent and does not involve the major autophosphorylation site Tyr(1173). c-Src activity is also induced by arsenic and is a prerequisite for the EGFR and ERK activation. Consistent with these in vitro observations, exposure of mice to arsenic in drinking water, which has been found previously to be associated with AP-1 activation and epithelial proliferation, induces EGFR and ERK activation in the urinary bladder. This response is also accompanied with an increase in c-Src levels interacting with EGFR. These findings represent a potential pathway for mediating arsenic-induced phenotypic changes in the uroepithelium.