Ras pathway activation in malignant mesothelioma
Ras pathway activation in malignant mesothelioma
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DOI：
10.1097/jto.0b013e31811f3aab
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发表时间：
2007-09-01
影响因子：
20.4
通讯作者：
Kratzke, Robert A.
中科院分区：
文献类型：
--
作者：
Patel, Manish R.;Jacobson, Blake A.;Kratzke, Robert A.
简介：Ras家族基因突变在恶性间皮瘤中是罕见的。Ras信号通路的激活在间皮瘤发病机制中的作用尚不清楚。方法：我们研究了Ras通路的激活状态和其他Ras相关激酶在一组人间皮瘤细胞系中的状态。此外，我们测试了抑制几种激酶途径对间皮瘤细胞增殖的影响。激酶信号的调节帽依赖translations.Results的潜在作用：在一般情况下，Ras-鸟苷三磷酸（GTP）是较高的间皮瘤细胞系相比，非转化的间皮瘤细胞系（LP 9）。此外，已知的Ras效应物，如细胞外调节激酶1/2，p38丝裂原活化蛋白激酶，和c-Jun N-末端激酶被发现在大多数测试的间皮瘤细胞系中是有活性的。与模拟处理的细胞相比，暴露于细胞外调节激酶1/2（U 0126）和c-Jun N-末端激酶（SP 600125）的特异性抑制剂显著降低了H2596和H2373细胞的增殖。SP 600125介导的c-Jun N-末端激酶抑制，但不是胞外调节激酶1/2抑制，导致4 E-BP 1的磷酸化减少，从而减少帽依赖activation.Conclusions：这些实验提供了一个基本原理，针对Ras和相关的信号通路在间皮瘤，也表明帽依赖性翻译作为一种机制，Ras诱导增殖在这种疾病。
Introduction: Mutations in Ras family genes are rare in malignant mesothelioma. The role of activation Of the Ras signaling pathway in the pathogenesis of mesothelioma is not clear.Methods: We studied the activation status of the Ras pathway and the status of other Ras-associated kinases in a panel of human mesotheliorna cell lines. In addition, we tested the effect of inhibition of several kinase pathways on mesotheliorna cell proliferation. The potential role of kinase signaling on the regulation of cap-dependent translation was also studied.Results: In general, Ras-guanosine triphosphate (GTP) was higher in mesotheliorna cell lines when compared with a nontransformed mesothelial cell line (LP9). Furthermore, known Ras effectors such as extracellular-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase were found to be active in most of the mesotheliorna cell lines tested. Exposure to specific inhibitors of extracellular-regulated kinase 1/2 (U0126) and c-Jun N-terminal kinase (SP600125) significantly decreased the proliferation of H2596 and H2373 cells compared with mock-treated cells. SP600125-mediated c-Jun N-terminal kinase inhibition, but not extracellular-regulated kinase 1/2 inhibition, resulted in a decrease in phosphorylation of 4E-BP1, consequently decreasing cap-dependent activation.Conclusions: These experiments provide a rationale for targeting Ras and associated signaling pathways in mesothelioma and also suggest cap-dependent translation as one mechanism by which Ras induces proliferation in this disease.