Association of β-catenin with P-Smad3 but not LEF-1 dissociates in vitro profibrotic from anti-inflammatory effects of TGF-β1

Abstract

SummaryTransforming growth factor b1 (TGF-b1) is known to be both anti-inflammatory and profibrotic. Cross-talk between TGF-b/Smad and Wnt/b-catenin pathways in epithelial-mesenchymal transition (EMT) suggests a specific role for b-catenin in profibrotic effects of TGFb1. However, no such mechanistic role has been demonstrated for b-catenin in the anti-inflammatory effects of TGF-b1. In the present study, we explored the role of b-catenin in the profibrotic and anti-inflammatory effects of TGF-b1 by using a cytosolic, but not membrane, b-catenin knockdown chimera (

Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk

“…[20][21][22][23][24] Our results were consistent with a direct interaction of the two pathways, and therefore, we tested whether b-catenin and smad3 directly interact in NRK-49F cells in response to TGFb. We treated NRK-49F cells with vehicle or TGFb for 48 hours.…”

β-Catenin/CBP–Dependent Signaling Regulates TGF-β–Induced Epithelial to Mesenchymal Transition of Lens Epithelial Cells

“…24,25 Inhibition of the β-catenin/CBP complex by the inhibitor ICG-001 39 prevents β-catenin and Smad3 interaction and has been shown to inhibit TGF-β–induced EMT in other systems. 25,26 We therefore utilized ICG-001 to determine whether disruption in β-catenin/CBP–dependent signaling in TGF-β2–treated explants can prevent fascin expression and EMT. Lens explants were treated with TGF-β2 in the presence or absence of ICG-001 (10 μM) for 48 hours.…”

“…25 For example, when disruption of the β-catenin/CBP complex was caused in alveolar epithelial cells by treatment with ICG-001, a small-molecule inhibitor that specifically inhibits β-catenin/CBP interaction and thereby prevents the interaction between β-catenin and Smad3, TGF-β–induced EMT was prevented. 25,26 These findings demonstrate the importance of CBP in β-catenin/Smad3 complex formation. 25 Further use of lithium chloride, a stimulant of β-catenin/TCF–dependent signaling, and ICG-001 in Smad reporter assay and TOP flash reporter assay demonstrated that β-catenin/CBP/Smad–dependent signaling, and not β-catenin/TCF/LEF–dependent signaling, was responsible for EMT and profibrotic effects in murine renal tubular epithelial cells.…”

“…23 However, the nature of the β-catenin signaling involved in the formation of these cataracts remains unclear. A number of recent reports have demonstrated that the interaction between β-catenin and Smad3, 24–26 as opposed to β-catenin/T-cell factor (TCF) interaction, 26 is critical for TGF-β–induced EMT. The formation of the β-catenin/Smad3 complex was further shown to be dependent on cyclic AMP response element–binding protein (CREB)-binding protein (CBP), a β-catenin transcriptional coactivator.…”

“…25 Further use of lithium chloride, a stimulant of β-catenin/TCF–dependent signaling, and ICG-001 in Smad reporter assay and TOP flash reporter assay demonstrated that β-catenin/CBP/Smad–dependent signaling, and not β-catenin/TCF/LEF–dependent signaling, was responsible for EMT and profibrotic effects in murine renal tubular epithelial cells. 26 …”