Selective activation of Src family kinases and JNK by low levels of chromium(VI)
Selective activation of Src family kinases and JNK by low levels of chromium(VI)
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DOI：
10.1016/s0041-008x(03)00188-1
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发表时间：
2003-08-01
影响因子：
3.8
通讯作者：
Barchowsky, A
中科院分区：
文献类型：
--
作者：
O'Hara, KA;Klei, LR;Barchowsky, A
吸入六价铬（Cr(VI)）通过尚不明确的机制引发肺部疾病和肺癌。在A549肺上皮细胞中对这些机制进行了研究，以验证无毒的Cr(VI)暴露会选择性激活细胞信号传导从而改变基因转录平衡这一假设。这些研究表明，相对于ERK或p38 MAP激酶，无毒剂量的Cr(VI)（10μM）会增加活性氧物质并选择性激活c - Jun N -末端激酶（JNK）。相反，只有有毒的、非选择性的外源性氧化剂水平才会刺激INK。然而，Cr(VI)和外源性H₂O₂（1 mM）引发的JNK激活都需要细胞内巯基氧化、Src家族激酶以及p130(cas)（Cas）的激活。Cr(VI)在仅含Src的成纤维细胞中不会模拟H₂O₂介导的对JNK的刺激，并且在A549细胞中不会激活Src或Yes。相反，在A549细胞中Fyn和Lck被激活，这表明针对Cr(VI)会激活特定的Src家族激酶。最后，研究证明Cr(VI)在体外可直接激活纯化的Fyn，且这种激活大多不需要产生氧化剂。这些数据表明，能够改变基因转录模式的无毒水平的Cr(VI)在激活细胞信号传导方面具有选择性，并且Cr(VI)可独立于活性氧物质的产生直接激活Src家族激酶。（C）2003爱思唯尔科学（美国）。版权所有。
Inhaled hexavalent chromium (Cr(VI)) promotes pulmonary disease and lung cancer through poorly defined mechanisms. These mechanisms were studied in A549 lung epithelial cells to investigate the hypothesis that nontoxic Cr(VI) exposures selectively activate cell signaling that shifts the balance of gene transcription. These studies demonstrated that nontoxic doses of Cr(VI) (10 muM) increased reactive oxygen species and selectively activated c-Jun N-terminal kinase (JNK), relative to ERK or p38 MAP kinase. In contrast, only toxic, nonselective levels of exogenous oxidants stimulated INK However, JNK activation in response to Cr(VI) and exogenous H2O2 (I mm) shared requirements for intracellular thiol oxidation, activation of Src family kinases, and p130(cas) (Cas). Cr(VI) did not mimic H2O2-mediated stimulation of JNK in fibroblasts containing only Src and did not activate Src or Yes in A549 cells. Instead, Fyn and Lck were activated in A549 cells, indicating activation of specific Src family kinases in response to Cr(VI). Finally, Cr(VI) was demonstrated to directly activate purified Fyn in vitro and the majority of this activation did not require oxidant generation. These data suggest that nontoxic levels of Cr(VI), which can shift patterns of gene transcription, are selective in their activation of cell signaling and that Cr(VI) can directly activate Src family kinases independently of reactive oxygen species generation. (C) 2003 Elsevier Science (USA). All rights reserved.