TGF‐β induces novel Lef‐1 splice variants through a Smad‐independent signaling pathway

Cordray, Pauline; Satterwhite, Daniel J.

doi:10.1002/dvdy.20275

Cited by 19 publications

(14 citation statements)

References 88 publications

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“…Concomitant LEF-1 and Smad3 HMG box domain binding has been demonstrated to account for cooperative ␤-catenin and transforming growth factor (TGF) pathway transcriptional control of target gene expression (50). Smaddependent TGF-␤ signaling contributes to EMT and is an important profibrotic stimulus (51). The present studies do not preclude an important interaction with TGF-␤ and other growth factors as part of the proliferative repair response in this model.…”

Section: Discussionmentioning

confidence: 63%

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

Douglas

Valle

Winn

et al. 2006

Am J Respir Cell Mol Biol

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Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical ␤-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and ␤-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O 2 ) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of ␤-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. ␤-Catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-␤-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury. Keywords: ␤-catenin; E-cadherin; lung injury repair; cell junctions; caspase Resolution of alveolar epithelial/capillary membrane damage after acute lung injury (ALI) requires coordinated and effective tissue reconstruction to reestablish a functional barrier. In particular, restoration of the normal air space architecture requires reconstitution of denuded type I alveolar epithelial cells that undergo apoptotic and necrotic death during the exudative phase of ALI. Coordination of extracellular matrix turnover and regeneration of type II epithelial cells is important in reestablishing surfactant production and ion transport (1). Orderly re-epithelialization suppresses fibroblast proliferation and matrix deposition after ALI (1, 2). However, resolution of ALI can result in disordered repair of the alveolus, characterized by impaired fibrinolysis of the in-

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Section: Discussionmentioning

confidence: 63%

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

Douglas

Valle

Winn

et al. 2006

Am J Respir Cell Mol Biol

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“…Lef-1 expression is characterized by the production of several isoforms, and Lef-1 transcripts arise through alternative (8,18,26,27,34). The fulllength Lef-1 transcript contains a large 5Ј untranslated region synthesized using a separate P1 promoter and utilizes a capindependent mechanism for translation of the full-length Lef-1 containing the ␤BD (30,34).…”

Section: Discussionmentioning

confidence: 99%

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

Amen

Liu

Vadlamudi

et al. 2007

Molecular and Cellular Biology

105

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Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with ␤-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and ␤-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length ␤-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated ␤-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and ␤-catenin in which the Lef-1 ␤-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, ␤-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and ␤-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and ␤-catenin.Pitx2 and Lef-1 encode two transcription factors whose expression can be regulated by early signaling events involved in numerous developmental programs. Pitx2 and Lef-1 are differentially expressed in many tissues, and they demonstrate overlapping expression during tooth development. Lef-1 can be activated by BMP, Wnt, Smads, and transforming growth factor ␤ signaling (18,32,33). Furthermore, Lef-1 transcriptional activity is regulated by its interaction with ␤-catenin. Secreted

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“…Growing evidence supports that in addition to the Smad family of proteins serving the primary role as intracellular effectors of TGF-h signaling, Smad-independent pathways also exist in the execution of TGF-h signals in target cells (36,37). Integrin-mediated interactions of cytoskeletal structures with the extracellular matrix can generate the required forces for cell movement, and sandwiched between them is the plasma membrane that may influence cellular processes such as activation of growth factor receptors and interaction of transmembrane signaling molecules with the cytoskeleton and extracellular matrix (38).…”

Section: Discussionmentioning

confidence: 99%

Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor β Signaling in Human Prostate Cancer Cells

Zhu¹,

Fukada

Zhu

et al. 2006

Cancer Research

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A proteomic analysis was pursued to identify new signaling effectors of transforming growth factor B1 (TGF-B1) that serve as potential intracellular effectors of its apoptotic action in human prostate cancer cells. The androgen-sensitive and TGF-B-responsive human prostate cancer cells, LNCaP TBRII, were used as in vitro model. In response to TGF-B, significant posttranslational changes in two proteins temporally preceded apoptotic cell death. TGF-B mediated the nuclear export of prohibitin, a protein involved in androgen-regulated prostate growth, to the cytosol in the LNCaP TBRII cells. Cofilin, a protein involved in actin depolymerization, cell motility, and apoptosis, was found to undergo mitochondrial translocation in response to TGF-B before cytochrome c release. Loss-offunction approaches (small interfering RNA) to silence prohibitin expression revealed a modest decrease in the apoptotic response to TGF-B and a significant suppression in TGF-B-induced cell migration. Silencing Smad4 showed that the cellular localization changes associated with prohibitin and cofilin action in response to TGF-B are independent of

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TGF‐β induces novel Lef‐1 splice variants through a Smad‐independent signaling pathway

Cited by 19 publications

References 88 publications

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor β Signaling in Human Prostate Cancer Cells

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