TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities

• Published in: Cellular signalling 2013-01, Vol.25 (1), p.264-268
• Main Authors: Samarakoon, Rohan, Overstreet, Jessica M., Higgins, Paul J.
• Format: Article
• Language: English
• Subjects: Cellular; Disorders; EGFR; Encoding; Fibrosis; Fibrosis - metabolism; Fibrosis - pathology; Genes; Humans; Inhibitors; Kinases; NADPH oxidases; NADPH Oxidases - metabolism; NOX; Oxidation-Reduction; p53; PAI-1; Plasminogen Activator Inhibitor 1 - metabolism; Reactive Oxygen Species - metabolism; Receptor, Epidermal Growth Factor - metabolism; ROS; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; SMADs; Stimulation; TGF-β; Transforming Growth Factor beta - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2012.10.003

During development of TGF-β1-initiated fibroproliferative disorders, NADPH oxidases (NOX family members) generate reactive oxygen species (ROS) resulting in downstream transcription of a subset genes encoding matrix structural elements and profibrotic factors. Prominent among the repertoire of disease-implicated genes is the TGF-β1 target gene encoding the potent profibrotic matricellular protein plasminogen activator inhibitor-1 (PAI-1 or SERPINE1). PAI-1 is the major physiologic inhibitor of the plasmin-based pericellular cascade and a causative factor in the development of vascular thrombotic and fibroproliferative disorders. ROS generation in response to TGF-β1 stimulation is rapid and precedes PAI-1 induction; engagement of non-SMAD (e.g., EGFR, Src kinase, MAP kinases, p53) and SMAD2/3 pathways are both required for PAI-1 expression and are ROS-dependent. Recent findings suggest a novel role for p53 in TGF-β1-induced PAI-1 transcription that involves ROS generation and p53/SMAD interactions. Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-β1 signaling. ► Emphasizes signaling events that regulate transcription of fibrosis-causative genes. ► ROS generation in response to TGF-β1 stimulation is rapid and precedes induction of the potent profibrotic factor plasminogen activator inhibitor-1 (PAI-1 or SERPINE1). ► Engagement of non-SMAD (e.g., EGFR, Src kinase, MAP kinases, p53) and SMAD2/3 pathways are both required for PAI-1 expression and are ROS-dependent. ► Recent findings suggest a novel role for p53 in TGF-β1-induced PAI-1 transcription that involves ROS generation and p53/SMAD interactions. ► Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-β 1 signaling.