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Review
. 2013 Jan;25(1):264-8.
doi: 10.1016/j.cellsig.2012.10.003. Epub 2012 Oct 11.

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

Rohan Samarakoon  1 , Jessica M Overstreet, Paul J Higgins
Affiliations
Review

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

Rohan Samarakoon et al. Cell Signal. 2013 Jan.

Abstract

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.

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Conflict of interest statement

Conflict of Interest: The authors declare that they have no conflicts of interests.

Figures

Figure 1
Figure 1. The plasmin-dependent/MMP axis in pericellular proteolytic control
uPA, tethered to its receptor (uPAR), converts plasminogen receptor- (PlgR-) bound plasminogen to the broad-spectrum protease plasmin that, in turn, activates several MMP family members. Collectively, plasmin and MMPs regulate, both in time and space, ECM proteolysis and stromal remodeling. TGF-β1-induced up-regulation of PAI-1 at the injury site can shift this proteolytic balance. In normal tissue repair, PAI-1 “titrates” the extent and locale of collagen matrix remodeling. Chronically-elevated PAI-1 levels in response to persistent profibrotic stimulation (e.g., TGF-β1, angiotensin II, elevated tissue glucose) commonly accompany the development of such diverse pathologies as, inflammation, hypertrophic scarring, atherosclerosis, thrombosis, myocardial infarction, diabetes, and the obesity-associated metabolic syndrome.
Figure 2
Figure 2. A model for ROS involvement in PAI-1 induction by TGF-β1
TGF-β1 receptor activation consequent to the ligand engagement initiates both Smad 2/3 (by phosphorylation of ALK5/TGF-β1 receptor 1 type) as well as non-Smad (e.g. EGFR, MAPK, Akt, Rho-ROCK) mediated signaling cascades with downstream consequences of gene expression (e.g. PAI-1, ECM molecules) as well as phenotypic modifications (e.g. excessive matrix deposition/fibrosis, epithelial plasticity, myofibroblast induction, proliferation, growth arrest and apoptosis). Rapid ROS generation consequent to TGF-β1 stimulation appears critical for initiation of non-SMAD (e.g. EGFR, Src) and modulation of SMAD (e.g. maintenance of SMAD phosphorylation) mediated signaling events. It is also becoming clear that p53 transcriptions factor integrates transcriptional contributions from both SMAD and non-SMAD cascades at the level of gene transcription (e.g. PAI-1) and ROS generation by TGF-β1 is crucial for p53 activation (by phosphorylation and acetylation).
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