Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells
Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells
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DOI：
10.1165/rcmb.2004-0198oc
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发表时间：
2005-01-01
影响因子：
6.4
通讯作者：
Reddy, SP
中科院分区：
文献类型：
--
作者：
Zhang, Q;Adiseshaiah, P;Reddy, SP
暴露于香烟烟雾（CS）可导致肺癌的发展，但这一过程的分子机制仍不清楚。鉴于激活蛋白1（AP-1）调节参与生理和病理生理过程的基因，我们研究了CS对Jun和Fos家族成员表达和调节的影响，使用非恶性的人支气管上皮细胞系，1HAEo。暴露于CS导致c-Jun，c-Fos和Fra-1的表达显著上调，但Fra-2，Jun-B和Jun-D表达不上调。由于Fra-1在各种肿瘤中过表达，并上调与肿瘤进展相关的基因，我们进一步阐明了控制CS刺激的Fra-1诱导的机制。CS刺激fra-1诱导主要在转录水平。然而，表皮生长因子受体（EGFR）特异性抑制剂，AG 1478，完全抑制CS刺激的FRA-1的表达。类似地，细胞外信号调节激酶（ERK）、c-Jun NH 2末端激酶（JNK）和p38激酶信号传导的特异性抑制剂显著抑制fra-1诱导。与这一发现一致，AG 1478阻断CS刺激的ERK、JNK和p38磷酸化。这些结果表明，EGFR激活的多激酶信号传导对于fra-1诱导是必不可少的。此外，GM 6001，抑制基质金属蛋白酶的活性，治疗细胞显着抑制CS刺激的EGF脱落，EGFR和ERK激酶磷酸化，和随后的fra-1诱导。总的来说，我们的研究结果表明，金属蛋白酶-EGFR介导的丝裂原活化蛋白激酶信号在控制CS诱导的FRA-1表达的强制性作用。
Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.