Loss of I?B kinase ? promotes myofibroblast transformation and senescence through activation of the ROS-TGF? autocrine loop.

ABSTRACT: Using forward and reverse genetics and global gene expression analyses, we explored the crosstalk between the I?B kinase ? (IKK?) and the transforming growth factor ? (TGF?) signaling pathways. We show that in vitro ablation of Ikk? in fibroblasts led to progressive ROS accumulation and TGF? activation, and ultimately accelerated cell migration, fibroblast-myofibroblast transformation and senescence. Mechanistically, the basal IKK? activity was required for anti-oxidant gene expression and redox homeostasis. Lacking this activity, IKK?-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 Tgf?2 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-TGF? loop IKK? plays a crucial role in the prevention of fibroblast-myofibroblast transformation and senescence.

SUBMITTER: Chen L 

PROVIDER: S-EPMC4853320 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature