The role of JunB in TGF-β-mediated repression of genes implicated in tissue homeostasis
Gervasi, Megan E.
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TGF-β is a multi-functional cytokine that regulates a number of genes involved in cellular behavior including proliferation, apoptosis, migration, adhesion, differentiation and modification of the microenvironment, making it one of the key players in maintenance of tissue homeostasis. De-regulation of homeostasis leads to the development of diseases such as fibrosis and cancer. The number of cellular responses regulated by TGF-β makes it an unsuitable therapeutic target. Understanding the molecular mechanism by which TGF-β regulates processes which contribute to maintenance and re-establishment of homeostasis following tissue damage would provide valuable insight into the pathogenesis of associated diseases as well as novel treatment options. The objective of this study was to investigate the molecular mechanism by which TGF-β represses expression of key factors in processes that contribute to maintenance of tissue homeostasis. TGF-β is known to repress Id2, a negative regulator of epithelial to mesenchymal transition (EMT), and phase II genes, which are important in regulating glutathione metabolism and utilization. This study identified several novel targets of TGF-β-Smad repression, IL-33 a potent pro-inflammatory cytokine, and several genes encoding enzymes involved in energy metabolism. Repression of these novel targets by TGF-β was confirmed in several cell lines. Investigation of the mechanism revealed that the basic leucine zipper protein JunB, a component of AP1 transcription factors, provides important input into regulation of these genes. We observed that depletion of JunB impaired repression of Id2, IL-33, Gclc, Gsta1 and Gstm1 (phase II genes) and ApoC2 and Aldh1a1 (energy metabolism genes). Repression of Id2 was associated with a block in key events in EMT: disruption of cell-cell junctions, remodeling of the actin cytoskeleton, formation of focal adhesions and expression of profibrotic proteins. Further investigation of the mechanism of repression of Id2 revealed that JunB cooperates with ATF3 in repression of Id2 through utilization of AP1 sites in the proximal promoter. These studies identify JunB as an important mediator of repression by TGF-β and support previous studies implicating JunB in processes that contribute to the development of fibrosis and cancer.