Ramos-Nino Maria E, Timblin Cynthia R, Mossman Brooke T
Department of Pathology, University of Vermont College of Medicine, Burlington 05405, USA.
Cancer Res. 2002 Nov 1;62(21):6065-9.
Mesothelioma is a unique and insidious tumor associated historically with occupational exposure to asbestos. The transcription factor, activator protein-1 (AP-1) is a major target of asbestos-induced signaling pathways. Here, we demonstrate that asbestos-induced mesothelial cell transformation is linked to increases in AP-1 DNA binding complexes and the AP-1 component, Fra-1. AP-1 binding to DNA was increased dramatically in mesothelioma cell lines in comparison to isolated rat pleural mesothelial (RPM) cells. Elevated levels of AP-1 complexes, including significant increases in c-Jun, JunB and Fra-1, were found in asbestos-exposed RPM cells, but only Fra-1 expression was significantly increased and protracted in both asbestos-exposed RPM cells and mesothelioma cell lines. Asbestos-induced Fra-1 expression in RPM cells was dependent on stimulation of the extracellular signal-regulated kinases (ERKs 1/2). Inhibition of ERK phosphorylation or transfection with dominant-negative fra-1 constructs reversed the transformed phenotype of mesothelioma cells and anchorage-independent growth in soft agar. In summary, we demonstrate that ERK-dependent Fra-1 is elevated in AP-1 complexes in response to asbestos fibers and is critical to the transformation of mesothelial cells.
间皮瘤是一种独特且隐匿的肿瘤，历史上一直与职业性接触石棉有关。转录因子激活蛋白-1（AP-1）是石棉诱导信号通路的主要靶点。在此，我们证明石棉诱导的间皮细胞转化与AP-1 DNA结合复合物及AP-1组分Fra-1的增加有关。与分离的大鼠胸膜间皮（RPM）细胞相比，间皮瘤细胞系中AP-1与DNA的结合显著增加。在暴露于石棉的RPM细胞中发现AP-1复合物水平升高，包括c-Jun、JunB和Fra-1显著增加，但仅Fra-1表达在暴露于石棉的RPM细胞和间皮瘤细胞系中均显著增加且持续时间延长。石棉在RPM细胞中诱导的Fra-1表达依赖于细胞外信号调节激酶（ERKs 1/2）的刺激。抑制ERK磷酸化或用显性负性fra-1构建体转染可逆转间皮瘤细胞的转化表型及在软琼脂中的非锚定依赖性生长。总之，我们证明在响应石棉纤维时，ERK依赖的Fra-1在AP-1复合物中升高，并且对间皮细胞的转化至关重要。
