Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop.
10.1007/s13238-015-0241-6
- Author:
Liang CHEN
1
;
Zhimin PENG
1
;
Qinghang MENG
1
;
Maureen MONGAN
1
;
Jingcai WANG
1
;
Maureen SARTOR
1
;
Jing CHEN
1
;
Liang NIU
1
;
Mario MEDVEDOVIC
1
;
Winston KAO
2
;
Ying XIA
3
Author Information
1. Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
2. Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
3. Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA. ying.xia@uc.edu.
- Publication Type:Journal Article
- Keywords:
IkB kinase β (IKKβ);
myofibroblast;
nuclear factor κB (NF-κB);
reactive oxygen species (ROS);
senescence;
transforming growth factors β (TGFβ)
- MeSH:
Adenoviridae;
genetics;
Animals;
Autocrine Communication;
physiology;
Cell Line;
Cell Movement;
Cellular Senescence;
Genetic Vectors;
genetics;
metabolism;
I-kappa B Kinase;
deficiency;
genetics;
metabolism;
JNK Mitogen-Activated Protein Kinases;
metabolism;
Mice;
Myofibroblasts;
cytology;
metabolism;
NADPH Oxidases;
metabolism;
Oxidative Stress;
Promoter Regions, Genetic;
Reactive Oxygen Species;
metabolism;
Signal Transduction;
Superoxide Dismutase;
genetics;
metabolism;
Transcription Factor AP-1;
metabolism;
Transforming Growth Factor beta;
genetics;
metabolism;
Up-Regulation
- From:
Protein & Cell
2016;7(5):338-350
- CountryChina
- Language:English
-
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.
