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

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.

c-Jun, at the crossroad of the signaling network

c-Jun, the most extensively studied protein of the activator protein-1 (AP-1) complex, is involved in numerous cell activities, such as proliferation, apoptosis, survival, tumorigenesis and tissue morphogenesis. Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper (bZIP) transcription factor that acts as homo- or heterodimer, binding to DNA and regulating gene transcription. Later on, it was shown that extracellular signals can induce post-translational modifications of c-Jun, resulting in altered transcriptional activity and target gene expression. More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk, amplify and integrate different signals for tissue development and disease. One example of such scheme is the autocrine amplification loop, in which signal-induced AP-1 activates the c-Jun gene promoter, while increased c-Jun expression feedbacks to potentiate AP-1 activity. Another example of such scheme, based on recent characterization of gene knockout mice, is that c-Jun integrates signals of several developmental pathways, including EGFR-ERK, EGFR-RhoA-ROCK, and activin B-MAP3K1-JNK for embryonic eyelid closure. After more than two decades of extensive research, c-Jun remains at the center stage of a molecular network with mysterious functional properties, some of which are yet to be discovered. In this article, we will provide a brief historical overview of studies on c-Jun regulation and function, and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.