scholarly journals Coordination of WNT signaling and ciliogenesis during odontogenesis by piezo type mechanosensitive ion channel component 1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Aya Miyazaki ◽  
Asuna Sugimoto ◽  
Keigo Yoshizaki ◽  
Keita Kawarabayashi ◽  
Kokoro Iwata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ion Channel ◽  
Wnt Signaling ◽  
Primary Cilia ◽  
Nuclear Translocation ◽  
Calcium Deposition ◽  
Marker Genes ◽  
Mechanical Forces ◽  
Odontoblast Differentiation ◽  
Mechanosensitive Ion Channel

Abstract Signal transmission from the mechanical forces to the various intracellular activities is a fundamental process during tissue development. Despite their critical role, the mechanism of mechanical forces in the biological process is poorly understood. In this study, we demonstrated that in the response to hydrostatic pressure (HP), the piezo type mechanosensitive ion channel component 1 (PIEZO1) is a primary mechanosensing receptor for odontoblast differentiation through coordination of the WNT expression and ciliogenesis. In stem cells from human exfoliated deciduous teeth (SHED), HP significantly promoted calcium deposition as well as the expression of odontogenic marker genes, PANX3 and DSPP, and WNT related-genes including WNT5b and WNT16, whereas HP inhibited cell proliferation and enhanced primary cilia expression. WNT signaling inhibitor XAV939 and primary cilia inhibitor chloral hydrate blocked the HP-induced calcium deposition. The PIEZO1 activator Yoda1 inhibited cell proliferation but induced ciliogenesis and WNT16 expression. Interestingly, HP and Yoda1 promoted nuclear translocation of RUNX2, whereas siRNA-mediated silencing of PIEZO1 decreased HP-induced nuclear translocation of RUNX2. Taken together, these results suggest that PIEZO1 functions as a mechanotransducer that connects HP signal to the intracellular signalings during odontoblast differentiation.

scholarly journals Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces

2016 ◽  
Vol 595 (1) ◽  
pp. 79-91 ◽  
Author(s):  
Fan Wang ◽  
Kaitlyn Knutson ◽  
Constanza Alcaino ◽  
David R. Linden ◽  
Simon J. Gibbons ◽  
...  
Keyword(s):  
Ion Channel ◽  
Cell Response ◽  
Mechanical Forces ◽  
Enterochromaffin Cell ◽  
Mechanosensitive Ion Channel

scholarly journals Analysis of the Mechanosensor Channel Functionality of TACAN

2021 ◽  
Author(s):  
Yiming Niu ◽  
Xiao Tao ◽  
George Vaisey ◽  
Paul Dominic B. Olinares ◽  
Hanan Alwaseem ◽  
...  
Keyword(s):  
Ion Channel ◽  
Physiological Function ◽  
Transmembrane Protein ◽  
Dimensional Structure ◽  
Mechanical Forces ◽  
Channel Activity ◽  
Fatty Acid Elongase ◽  
Membrane Reconstitution ◽  
3 Dimensional ◽  
Mechanosensitive Ion Channel

Mechanosensitive ion channels mediate transmembrane ion currents activated by mechanical forces. A mechanosensitive ion channel called TACAN was recently reported. We began to study TACAN with the intent to understand how it senses mechanical forces and functions as an ion channel. Using cellular patch-recording methods we failed to identify mechanosensitive ion channel activity. Using membrane reconstitution methods we found that TACAN, at high protein concentrations, produces non-selective, heterogeneous conduction levels that are not mechanosensitive and are most consistent with disruptions of the lipid bilayer. We determined the structure of TACAN using single particle cryo-EM and observe that it forms a symmetrical dimeric transmembrane protein. Each protomer contains an intracellular-facing cleft with a coenzyme-A co-factor, confirmed by mass spectrometry. The TACAN protomers are related in 3-dimensional structure to a fatty acid elongase, ELOVL. Whilst its physiological function remains unclear, we anticipate that TACAN is not a mechanosensitive ion channel.

Bortezomib Induces Osteoblast Differentiation Via Wnt-Independent Activation of Beta-catenin/TCF Signaling

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 846-846
Author(s):  
Ya-wei Qiang ◽  
Bo Hu ◽  
Yu Chen ◽  
Ying Zhong ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Wnt Signaling ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Receptor Expression ◽  
Calcium Deposition ◽  
Beta Catenin ◽  
Matrix Mineralization

Abstract Bone loss in multiple myeloma (MM) and other conditions represents a serious clinical problem, and extensive research is being conducted to develop new drugs that target signaling cascades whose disruption is known to cause bone loss. Inhibition of Wnt/beta-catenin/TCF signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts. Osteolysis in MM and several other diseases has recently been linked to the suppression of Wnt/beta-catenin/TCF signaling. The antitumor activity of the proteasome inhibitor bortezomib in MM has been linked to its bone anabolic effects. However, the molecular basis of bortezomib’s action on bone is not well characterized. Here we show that bortezomib activates the beta-catenin/TCF pathway in murine and human osteoblast progenitors and human mesenchymal stem cells derived from bone marrow of healthy donors and patients with MM, leading to their subsequent differentiation in-vitro as assessed by matrix mineralization and calcium deposition. Pull-down assays followed by immunoblotting and immunofluorescence microscopy revealed that bortezomib induced stabilization of beta-catenin in both the cytoplasm and nucleus. Nuclear translocation of stabilized beta-catenin was associated with the activation of beta-catenin/TCF transcriptional activity as detected by luciferase activity from TOPFLASH reporter constructs. This activation was not dependent on the drug inducing Wnt ligand or receptor expression, the suppression of Wnt signaling inhibitors or change in disheveled protein levels. Synergy experiments showed that recombinant Wnt3a or LiCl-induced inactivation of GSK3beta did not enhance bortezomib-induced changes in TCF activity. Matrix mineralization was not accompanied by the induction of alkaline phosphatase or osteoprotegerin, which can be activated by Wnt3a in these cell types. Blocking the activation of beta-catenin/TCF signaling by dominant negative TCF attenuated bortezomib-induced matrix mineralization. These results add to the growing body of evidence demonstrating a critical role of the Wnt/beta-catenin pathway in bone biology and provide mechanistic insights into the recently recognized bone anabolic effects of bortezomib. As the effects of bortezomib completely bypass all known regulatory mechanisms governing Wnt signaling, these data also provide a strong rationale for the use of bortezomib in the treatment of diseases linked to suppression of Wnt/beta-catenin signaling.

scholarly journals Bortezomib induces osteoblast differentiation via Wnt-independent activation of β-catenin/TCF signaling

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4319-4330 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Bo Hu ◽  
Yu Chen ◽  
Ying Zhong ◽  
Bingyin Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Wnt Signaling ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
Calcium Deposition ◽  
Canonical Wnt Signaling ◽  
Matrix Mineralization ◽  
Canonical Wnt

Abstract Inhibition of Wnt/β-catenin/T-cell factor (TCF) signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts (OBs). Osteolysis in multiple myeloma (MM) is related to the suppression of canonical Wnt signaling caused by DKK1, a soluble inhibitor of this pathway secreted by MM cells. Bortezomib (Bzb) can induce OB differentiation in vitro and in vivo and its anti-MM efficacy linked to bone anabolic effects. However, the molecular basis of the action of Bzb on bone is not completely understood. In the present study, we show that Bzb promotes matrix mineralization and calcium deposition by osteoprogenitor cells and primary mesenchymal stem cells via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting and immunofluorescence, we found that Bzb induced stabilization of β-catenin. Nuclear translocation of stabilized β-catenin was associated with β-catenin/TCF transcriptional activity that was independent of the effects of Wnt ligand-receptor-induced signaling or GSK3β activation. Blocking the activation of β-catenin/TCF signaling by dominant negative TCF attenuated Bzb-induced matrix mineralization. These results provide evidence that Bzb induces OB differentiation via Wnt-independent activation of β-catenin/TCF pathway and suggest that proteasome inhibition therapy in MM may function in part by subverting tumor-induced suppression of canonical Wnt signaling in the bone microenvironment.

scholarly journals Analysis of the Mechanosensor Channel Functionality of TACAN

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yiming Niu ◽  
Xiao Tao ◽  
George Vaisey ◽  
Paul D B Olinares ◽  
Hanan Alwaseem ◽  
...  
Keyword(s):  
Ion Channel ◽  
Physiological Function ◽  
Transmembrane Protein ◽  
Dimensional Structure ◽  
Mechanical Forces ◽  
Channel Activity ◽  
Fatty Acid Elongase ◽  
Membrane Reconstitution ◽  
3 Dimensional ◽  
Mechanosensitive Ion Channel

Mechanosensitive ion channels mediate transmembrane ion currents activated by mechanical forces. A mechanosensitive ion channel called TACAN was recently reported. We began to study TACAN with the intent to understand how it senses mechanical forces and functions as an ion channel. Using cellular patch-recording methods we failed to identify mechanosensitive ion channel activity. Using membrane reconstitution methods we found that TACAN, at high protein concentrations, produces heterogeneous conduction levels that are not mechanosensitive and are most consistent with disruptions of the lipid bilayer. We determined the structure of TACAN using single particle cryo-EM and observe that it forms a symmetrical dimeric transmembrane protein. Each protomer contains an intracellular-facing cleft with a coenzyme-A cofactor, confirmed by mass spectrometry. The TACAN protomers are related in 3-dimensional structure to a fatty acid elongase, ELOVL. Whilst its physiological function remains unclear, we anticipate that TACAN is not a mechanosensitive ion channel.

scholarly journals Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
K. M. Lawrence ◽  
R. C. Jones ◽  
T. R. Jackson ◽  
R. L. Baylie ◽  
B. Abbott ◽  
...  
Keyword(s):  
Ion Channel ◽  
Mechanosensitive Ion Channel

scholarly journals The Dickkopf1 and FOXM1 positive feedback loop promotes tumor growth in pancreatic and esophageal cancers

Oncogene ◽  
2021 ◽  
Author(s):  
Hirokazu Kimura ◽  
Ryota Sada ◽  
Naoki Takada ◽  
Akikazu Harada ◽  
Yuichiro Doki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cancer Cell ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Ductal Adenocarcinoma ◽  
Cancer Cell Proliferation ◽  
Positive Feedback Loop ◽  
Dkk1 Expression ◽  
Foxm1 Expression

AbstractDickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5ʹ-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.

scholarly journals Glucagon-Like Peptide-2 Activates β-Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 291-301 ◽  
Author(s):  
Philip E. Dubé ◽  
Katherine J. Rowland ◽  
Patricia L. Brubaker
Keyword(s):  
Cell Proliferation ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Crypt Cell ◽  
Acute Administration ◽  
Intestinal Crypt ◽  
Crypt Cell Proliferation ◽  
Igf I ◽  
Glucagon Like Peptide ◽  
Crypt Cells

Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because β-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly2-GLP-2 or LR3-IGF-I (positive control) for 0.5–4 h. Nuclear translocation of β-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3β and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased β-catenin nuclear translocation in non-Paneth crypt cells by 72 ± 17% (P < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 ± 20 and 376 ± 170%, respectively (P < 0.05–0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates β-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in β-catenin.

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