Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop

Protein & Cell

卷:7

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