Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production
Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production
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DOI：
10.1016/j.taap.2004.04.023
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发表时间：
2004-11-01
影响因子：
3.8
通讯作者：
Hudson, LG
中科院分区：
文献类型：
--
作者：
Cooper, KL;Myers, TA;Hudson, LG
砷的皮肤毒性是公认的，流行病学研究发现与砷暴露相关的角质形成细胞肿瘤(基底细胞和鳞状细胞癌)的发病率增加。目前对砷介导的皮肤癌发生机制知之甚少，但丝裂原活化蛋白(MAP)激酶的激活及其下游靶基因的调控可能与肿瘤的发生和发展有关。在这项研究中，我们研究了亚砷酸盐对HaCat细胞(一种自然永生化的人角质形成细胞系)细胞外信号调节激酶(ERK)和应激相关激酶p38的激活。亚砷酸盐浓度大于或等于100微米，可刺激p38和ERK蛋白激酶的快速激活。然而，延长暴露时间(24小时)，在低浓度的亚砷酸盐下可检测到持续刺激p38和ERK的MAP激酶。尽管ERK和p38的激活具有相似的时间和浓度依赖关系，但这两种MAP激酶的激活机制不同。亚砷酸盐对ERK的激活完全依赖于表皮生长因子(EGF)受体的催化活性，部分依赖于Src家族的激酶活性。相反，p38的激活不依赖于EGF受体或Src家族的激酶活性。亚砷酸盐刺激的MAP激酶信号转导导致AP-1调节的基因产物基质金属蛋白(MMP9)的产生增加。抑制EGF受体或MAP激酶信号转导可阻止亚砷酸盐诱导的基质金属蛋白酶-9表达。这些研究表明，表皮生长因子受体的激活是亚砷酸盐介导的角质形成细胞信号转导和基因表达的一个组成部分，低摩尔浓度的亚砷酸盐在长期暴露时会刺激关键的信号通路。砷对MAP激酶的激活及其对c-fos、c-jun和基质降解酶等基因的调控可能在砷诱导的皮肤癌发生中起重要作用。(C)2004 Elsevier Inc.保留所有权利。
The dermatotoxicity of arsenic is well established and epidemiological studies identify an increased incidence of keratinocytic tumors (basal cell and squamous cell carcinoma) associated with arsenic exposure. Little is known about the underlying mechanisms of arsenic mediated skin carcinogenesis, but activation of mitogen-activated protein (MAP) kinases and subsequent regulation of downstream target genes may contribute to tumor promotion and progression. In this study, we investigated activation of the extracellular signal regulated kinase (ERK) and the stress-associated kinase p38 by arsenite in HaCat cells, a spontaneously immortalized human keratinocyte cell line. Arsenite concentrations greater than or equal to100 muM stimulate rapid activation of p38 and ERK MAP kinases. However, upon extended exposure (24 h), persistent stimulation of p38 and ERK MAP kinases was detected at low micromolar concentrations of arsenite. Although ERK and p38 were activated with similar time and concentration dependence, the mechanism of activation differed for these two MAP kinases. ERK activation by arsenite was fully dependent on the catalytic activity of the epidermal growth factor (EGF) receptor and partially dependent on Src-family kinase activity. In contrast, p38 activation was independent of EGF receptor or Src-family kinase activity. Arsenite-stimulated MAP kinase signal transduction resulted in increased production of matrix metalloprotemase (MMP)-9, an AP-1 regulated gene product. MMP-9 induction by arsenite was prevented when EGF receptor or MAP kinase signaling was inhibited. These studies indicate that EGF receptor activation is a component of arsenite-mediated signal transduction and gene expression in keratinocytes and that low micromolar concentrations of arsenite stimulate key signaling pathways upon extended exposure. Stimulation of MAP kinase cascades by arsenic and subsequent regulation of genes including c-fos, c-jun, and the matrix degrading proteases may play an important role in arsenic-induced skin carcinogenesis. (C) 2004 Elsevier Inc. All rights reserved.