Interactions Between β-Catenin and Transforming Growth Factor-β Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)

Zhou, Baosen; Liu, Yixin; Kahn, Michaël; Ann, David K.; Han, Arum; Wang, Hongjun; Nguyen, Carvell T.; Flodby, Per; Zhong, Qian; Krishnaveni, Manda S.; Liebler, Janice M.; Minoo, Parviz; Crandall, Edward D.; Borok, Zea

doi:10.1074/jbc.m111.276311

Cited by 237 publications

(205 citation statements)

References 60 publications

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“…[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.…”

Section: Canonical Wnt Signaling Is Necessary For Tgfbmediated Myofibsupporting

confidence: 71%

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

Maarouf

Aravamudhan

Rangarajan

et al. 2016

Journal of the American Society of Nephrology

111

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AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-induced epithelial secretion of profibrotic factors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFbdependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wnt1 expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptor b-positive myofibroblasts isolated from these kidneys exhibited increased canonical Wnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelialderived Wnt ligand is sufficient to drive interstitial fibrosis provides strong support for the maladaptive repair hypothesis in the AKI to CKD transition.

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Section: Canonical Wnt Signaling Is Necessary For Tgfbmediated Myofibsupporting

confidence: 71%

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

Maarouf

Aravamudhan

Rangarajan

et al. 2016

Journal of the American Society of Nephrology

111

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“…The transcription co-factors, especially those that are cell type specific, not only stabilize Smad association with DNA, but may also determine which specific gene(s) that the Smad complex targets. b-Catenin of the Wnt pathway has been found to form b-catenin/Smad complexes in TGF-b-induced EMT in lung alveolar epithelial cells (Kim et al, 2009a;Zhou et al, 2012) and to facilitate b-catenin transcriptional activity in chondrocytes (Zhang et al, 2010). However, the detailed molecular mechanisms remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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

Tian

Zhang

Tan

et al. 2013

Journal of Cell Science

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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 (

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“…Recently, ICG-001 has shown to be able to block EMT (epithelial to mesenchymal transition) induced by TGF 1 in a RLE-6TN rat lung epithelial-T-antigen negative cell line. [435]. ICG-001 has reached Phase 1 clinical trials [436].…”

Section: The -Catenin Tcf/lef Transcription Complexmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Interactions Between β-Catenin and Transforming Growth Factor-β Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)

Cited by 237 publications

References 60 publications

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

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

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

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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