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Protein & Cell ; (12): 338-350, 2016.
Article Dans Anglais | WPRIM | ID: wpr-757141

Résumé

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.


Sujets)
Animaux , Souris , Adenoviridae , Génétique , Communication autocrine , Physiologie , Lignée cellulaire , Mouvement cellulaire , Vieillissement de la cellule , Vecteurs génétiques , Génétique , Métabolisme , I-kappa B Kinase , Génétique , Métabolisme , JNK Mitogen-Activated Protein Kinases , Métabolisme , Myofibroblastes , Biologie cellulaire , Métabolisme , NADPH oxidase , Métabolisme , Stress oxydatif , Régions promotrices (génétique) , Espèces réactives de l'oxygène , Métabolisme , Transduction du signal , Superoxide dismutase , Génétique , Métabolisme , Facteur de transcription AP-1 , Métabolisme , Facteur de croissance transformant bêta , Génétique , Métabolisme , Régulation positive
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