Protein & Cell | 卷:7 |
Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop | |
Maureen Mongan1  Maureen Sartor1  Jing Chen1  Liang Chen1  Qinghang Meng1  Jingcai Wang1  Mario Medvedovic1  Zhimin Peng1  Liang Niu1  Ying Xia1  Winston Kao2  | |
[1] Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center; | |
[2] Department of Ophthalmology, University of Cincinnati Medical Center; | |
关键词: IkB kinase β (IKKβ); nuclear factor κB (NF-κB); transforming growth factors β (TGFβ); reactive oxygen species (ROS); myofibroblast; senescence; | |
DOI : 10.1007/s13238-015-0241-6 | |
来源: DOAJ |
【 摘 要 】
ABSTRACT 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.
【 授权许可】
Unknown