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

Samarakoon R, Overstreet JM, Higgins PJ
Cell Signal. 2013 25 (1): 264-8

PMID: 23063463 · PMCID: PMC3508263 · 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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (12)

ErbB Receptors Fibrosis Humans NADPH Oxidases Oxidation-Reduction Plasminogen Activator Inhibitor 1 Reactive Oxygen Species Signal Transduction Smad2 Protein Smad3 Protein Transforming Growth Factor beta Tumor Suppressor Protein p53

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