Chen Liang, Peng Zhimin, Meng Qinghang, Mongan Maureen, Wang Jingcai, Sartor Maureen, Chen Jing, Niu Liang, Medvedovic Mario, Kao Winston, Xia Ying
Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
Protein Cell. 2016 May;7(5):338-50. doi: 10.1007/s13238-015-0241-6. Epub 2016 Mar 5.
Using forward and reverse genetics and global gene expression analyses, we explored the crosstalk between the IκB kinase β (IKKβ) and the transforming growth factor β (TGFβ) signaling pathways. We show that in vitro ablation of Ikkβ in fibroblasts led to progressive ROS accumulation and TGFβ activation, and ultimately accelerated cell migration, fibroblast-myofibroblast transformation and senescence. Mechanistically, the basal IKKβ activity was required for anti-oxidant gene expression and redox homeostasis. Lacking this activity, IKKβ-null cells showed ROS accumulation and activation of stress-sensitive transcription factor AP-1/c-Jun. AP-1/c-Jun activation led to up-regulation of the Tgfβ2 promoter, which in turn further potentiated intracellular ROS through the induction of NADPH oxidase (NOX). These data suggest that by blocking the autocrine amplification of a ROS-TGFβ loop IKKβ plays a crucial role in the prevention of fibroblast-myofibroblast transformation and senescence.
我们运用正向和反向遗传学以及全基因组基因表达分析方法，探究了IκB激酶β（IKKβ）与转化生长因子β（TGFβ）信号通路之间的相互作用。我们发现，在体外实验中，成纤维细胞中Ikkβ的缺失会导致活性氧（ROS）逐渐积累以及TGFβ激活，最终加速细胞迁移、成纤维细胞向肌成纤维细胞的转化以及细胞衰老。从机制上来说，抗氧化基因的表达和氧化还原稳态需要基础的IKKβ活性。缺乏这种活性时，IKKβ基因敲除细胞会出现ROS积累以及应激敏感转录因子AP-1/c-Jun的激活。AP-1/c-Jun的激活导致Tgfβ2启动子上调,进而通过诱导NADPH氧化酶（NOX）进一步增强细胞内ROS水平。这些数据表明，IKKβ通过阻断ROS-TGFβ环路的自分泌放大，在预防成纤维细胞向肌成纤维细胞的转化和细胞衰老中发挥关键作用。
Zotero 插件
