δEF1 Mediates TGF-β Signaling in Vascular Smooth Muscle Cell Differentiation

Nishimura, Go; Manabe, Ichiro; Tsushima, Kensuke; Fujiu, Katsuhito; Oishi, Yumiko; Imai, Yasushi; Maemura, Koji; Miyagishi, Makoto; Higashi, Youichirou; Kondoh, Hisato; Nagai, Ryozo

doi:10.1016/j.devcel.2006.05.011

Cited by 136 publications

(112 citation statements)

References 32 publications

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“…On SMCs, TGF-β1 suppresses proliferation while induces differentiation. 14,15 TGF-β2 plays an essential role in the valve formation during embryonic development via endothelial-mesenchymal transition. 16 TGF-β3 negatively regulates TGF-β1-mediated extracellular matrix deposition.…”

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confidence: 99%

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Zeng

Yang

et al. 2015

ATVB

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Objective-Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes. Approach and Results-In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositolrequiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation. Conclusions-This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation. under stress conditions. [21][22][23] Under ER stress conditions, XBP1 mRNA undergoes unconventional splicing through an ER-resident kinase that possesses ribonuclease activity, the inositol-requiring enzyme 1 α (IRE1α). 24 Our recent studies and reports from other groups showed that physiological stimuli such as vascular endothelial cell growth factor could trigger XBP1 splicing in an ER stress response-independent manner. [25][26][27][28] In endothelial cells (ECs), XBP1 splicing plays diverse roles, including cell proliferation, 26 autophagy response, 29 and apoptosis. 30 In SMCs, bone morphogenetic protein-2 was reported to activate XBP1 splicing, 31 but the exact role of XBP1 in SMCs still remains unclear. In this study, we demonstrated that XBP1 splicing is crucial in PDGF-BB-induced SMC proliferation and contributes to neointima formation after vascular injury. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Vascular Injury Increased XBP1 Expression and SplicingIn response to vascular injury, vascular SMCs will be activated undergoing migration, proliferation, and apoptosis. 32 To test whether XBP1 was involved in SMC activation, femoral artery injury model was introduced into the right side of C57Bl/6 mice. The injured vessels were harvested at day 1, and day 3 post surgery, whereas the left uninjured vessels were collected as control. Double immunofluorescence staining with anti-α SMC actin and antispliced XBP1 (XBP1s) or unspliced XBP1 (XBP1u) antibodies were performed on the cryo-sections. As shown in Figure 1A, low levels of XBP1s and XBP1u were detected in the uninjure...

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confidence: 99%

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Zeng

Yang

et al. 2015

ATVB

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“…38 ZEB1 is induced by TGFb during smooth muscle differentiation, in which it interacts with Smad3 and SRF to transactivate the genes encoding smooth muscle a-actin and smooth muscle myosin heavy chain. 39 Furthermore, overexpression of ZEB1 in MCF-10A cells reduced E-cadherin and p65 expression and displayed an EMT phenotype. 31 In our present study, we show that TBK1 can attenuate radiation-induced upregulation of ZEB1.…”

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confidence: 99%

Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

Huang

et al. 2014

Laboratory Investigation

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Radiotherapy is an effective treatment method for lung cancer, particularly when the disease is at an advanced stage. However, previous researchers have observed that the majority of patients with conventional radiation therapy develop distant metastases and succumb to the disease. Thus, identifying and understanding novel pathways for the development of new therapeutic targets is a major goal in research on pulmonary neoplasms. Recent studies suggest that epithelial-mesenchymal transition (EMT) is the most important contributor to cancer metastasis. Induction of this complex process requires endogenously produced microRNAs; specifically, downregulation of the miRNA-200c causes an induction of EMT. We recently identified the tank-binding kinase-1 (TBK1) as a downstream effector of the miR-200c-driven pathway, but the biological function of TBK1 in EMT remains unknown. In this study, we tested whether TBK1 has a role in radiation-induced EMT and identified associated potential mechanisms. Human alveolar type II epithelial carcinoma A549 cells were irradiated with 60 Co g-rays. Western blotting revealed a time-and dose-dependent decrease in E-cadherin with a concomitant increase in vimentin after radiation, suggesting that the epithelial cells acquired a mesenchymal-like morphology. TBK1 siRNA significantly inhibited radiationinduced suppression of the epithelial marker E-cadherin and upregulation of the mesenchymal marker vimentin. The invasion and migratory potential of lung cancer cells upon radiation treatment was also reduced by TBK1 knockdown. Furthermore, radiation-induced EMT attenuated by TBK1 depletion was partially dependent on transcriptional factor ZEB1 expression. Finally, we found glycogen synthase kinase-3b (GSK-3b) is involved in regulation of radiation-induced EMT by TBK1. Thus, our findings reveal that TBK1 signaling regulates radiation-induced EMT by controlling GSK-3b phosphorylation and ZEB1 expression. TBK1 may therefore constitute a useful target for treatment of radiotherapy-induced metastasis diseases.

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“…Myocardin, an important coactivator of serum response factor, was shown to potently enhance TGF-β/Smad3-mediated activation of SM22α actin transcription [62]. The zinc finger E-box binding transcription factor DeltaEF1 was also shown to have an important effector role in this respect by forming a complex with serum response factor and Smad3 [63]. TGF-β-induced growth inhibition of vascular SMCs was found to be ALK5-mediated via both Smad3-dependent and p38 MAP kinase-dependent signaling pathways [64].…”

Section: Role Of Tgf-β Signaling In Vascular Smcsmentioning

confidence: 99%

TGF-β signaling in vascular biology and dysfunction

2008

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Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.

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δEF1 Mediates TGF-β Signaling in Vascular Smooth Muscle Cell Differentiation

Cited by 136 publications

References 32 publications

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

TGF-β signaling in vascular biology and dysfunction

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