scholarly journals Eukaryotic initiation factor 4A3 inhibits Wnt/β-catenin signaling and regulates axis formation in zebrafish embryos

Development ◽  
2021 ◽  
Author(s):  
Bo Wang ◽  
Xiaozhi Rong ◽  
Yumei Zhou ◽  
Yunzhang Liu ◽  
Jiqin Sun ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Target Genes ◽  
Transcription Activation ◽  
Initiation Factor ◽  
Exon Junction Complex ◽  
Axis Formation ◽  
Zebrafish Embryos ◽  
Eukaryotic Initiation Factor ◽  
Wnt Inhibitor ◽  
Transcriptional Complex

A key step in the activation of canonical Wnt signaling is the interaction between β-catenin and Tcf/Lefs that forms the transcription activation complex and facilitates the expression of target genes. Eukaryotic initiation factor 4A3 (EIF4A3) is an ATP-dependent DEAD box-family RNA helicase and acts as a core subunit of the exon junction complex (EJC) to control a series of RNA posttranscriptional processes. In this study, we uncovered that EIF4A3 functions as a Wnt inhibitor by interfering with the formation of β-catenin/Tcf transcription activation complex. As Wnt stimulation increases, accumulated β-catenin displaces EIF4A3 from a transcriptional complex with Tcf/Lef, allowing the active complex to facilitate the expression of target genes. In zebrafish embryos, eif4a3 depletion inhibited the development of the dorsal organizer and pattern formation of the anterior neuroectoderm by increasing Wnt/β-catenin signaling. Conversely, overexpression of eif4a3 decreased Wnt/β-catenin signaling and inhibited the formation of the dorsal organizer before gastrulation. Our results reveal novel roles of EIF4A3 in the inhibition of Wnt signaling and the regulation of embryonic development in zebrafish.

scholarly journals Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein

2000 ◽  
Vol 14 (14) ◽  
pp. 1741-1749 ◽  
Author(s):  
Ken-ichi Tago ◽  
Tsutomu Nakamura ◽  
Michiru Nishita ◽  
Junko Hyodo ◽  
Shin-ichi Nagai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factors ◽  
Embryonic Development ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Target Genes ◽  
Wnt Signaling Pathway ◽  
Axis Formation ◽  
Interacting Protein

Wnt signaling has an important role in both embryonic development and tumorigenesis. β-Catenin, a key component of the Wnt signaling pathway, interacts with the TCF/LEF family of transcription factors and activates transcription of Wnt target genes. Here, we identify a novel β-catenin-interacting protein, ICAT, that was found to inhibit the interaction of β-catenin with TCF-4 and represses β-catenin–TCF-4-mediated transactivation. Furthermore, ICAT inhibited Xenopus axis formation by interfering with Wnt signaling. These results suggest that ICAT negatively regulates Wnt signaling via inhibition of the interaction between β-catenin and TCF and is integral in development and cell proliferation.

scholarly journals Structural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)

2011 ◽  
Vol 286 (22) ◽  
pp. 19204-19214 ◽  
Author(s):  
Kristina Tanneberger ◽  
Astrid S. Pfister ◽  
Vitezslav Kriz ◽  
Vitezslav Bryja ◽  
Alexandra Schambony ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Wnt Signaling ◽  
Adenomatous Polyposis Coli ◽  
Target Genes ◽  
Functional Characterization ◽  
Negative Control ◽  
Membrane Localization ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Wnt Inhibitor

Amer1/WTX binds to the tumor suppressor adenomatous polyposis coli and acts as an inhibitor of Wnt signaling by inducing β-catenin degradation. We show here that Amer1 directly interacts with the armadillo repeats of β-catenin via a domain consisting of repeated arginine-glutamic acid-alanine (REA) motifs, and that Amer1 assembles the β-catenin destruction complex at the plasma membrane by recruiting β-catenin, adenomatous polyposis coli, and Axin/Conductin. Deletion or specific mutations of the membrane binding domain of Amer1 abolish its membrane localization and abrogate negative control of Wnt signaling, which can be restored by artificial targeting of Amer1 to the plasma membrane. In line, a natural splice variant of Amer1 lacking the plasma membrane localization domain is deficient for Wnt inhibition. Knockdown of Amer1 leads to the activation of Wnt target genes, preferentially in dense compared with sparse cell cultures, suggesting that Amer1 function is regulated by cell contacts. Amer1 stabilizes Axin and counteracts Wnt-induced degradation of Axin, which requires membrane localization of Amer1. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the β-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.

scholarly journals The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment

2013 ◽  
Vol 305 (9) ◽  
pp. E1124-E1133 ◽  
Author(s):  
Gabriel J. Wilson ◽  
Piyawan Bunpo ◽  
Judy K. Cundiff ◽  
Ronald C. Wek ◽  
Tracy G. Anthony
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Target Genes ◽  
Binding Protein ◽  
Lymphoblastic Leukemia ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Triglyceride Accumulation ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2

Asparaginase is an important drug in the treatment regimen for acute lymphoblastic leukemia. Asparaginase depletes circulating asparagine and glutamine, activating an amino acid stress response (AAR) involving phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible kinase 2 (GCN2). We hypothesized that GCN2 functions to mitigate hepatic stress during asparaginase therapy by activating the AAR. To test this idea, C57BL/6J wild-type mice ( Gcn2+/+) and those deleted for Gcn2 ( Gcn2−/−) were injected with asparaginase or saline excipient one time daily for 1 or 6 days. In liver, increased phosphorylation of eIF2 and mRNA expression of AAR target genes activating transcription factor 4, asparagine synthetase, eIF4E-binding protein 1, and CAAT enhancer-binding protein homologous protein were significantly blunted or blocked in the liver of G cn2−/− mice. Loss of AAR during asparaginase coincided with increases in mammalian target of rapamycin signaling, hepatic triglyceride accumulation, and DNA damage in association with genetic markers of oxidative stress ( glutathione peroxidase) and inflammation ( tumor necrosis factor alpha-α). Although asparaginase depleted circulating asparagine in both Gcn2+/+ and Gcn2−/− mice, all other amino acids, including plasma glutamine, were elevated in the plasma of Gcn2−/− mice. This study shows that loss of GCN2 promotes oxidative stress and inflammatory-mediated DNA damage during asparaginase therapy, suggesting that patients with reduced or dysfunctional AAR may be at risk of developing hepatic complications during asparaginase treatment.

scholarly journals Active Src Elevates the Expression of β-Catenin by Enhancement of Cap-Dependent Translation

2005 ◽  
Vol 25 (12) ◽  
pp. 5031-5039 ◽  
Author(s):  
Rotem Karni ◽  
Yael Gus ◽  
Yuval Dor ◽  
Oded Meyuhas ◽  
Alexander Levitzki
Keyword(s):  
Cyclin D1 ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Wnt Pathway ◽  
Target Genes ◽  
Mtor Pathway ◽  
Initiation Factor ◽  
Erk Pathway ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E

ABSTRACT The proto-oncogene pp60c-Src (c-Src) is activated in many types of cancer and contributes to the transformed phenotype of the tumor, although its role is not yet fully understood. Here we report that active Src elevates the levels of β-catenin by enhancing cap-dependent translation. Src induces phosphorylation of the eukaryotic initiation factor 4E via the Ras/Raf/ERK pathway and the phosphorylation of its inhibitor 4E-BP1 via the PI3K/mTOR pathway. Activated Src enhances the accumulation of nuclear β-catenin and enhances its transcriptional activity, elevating target genes such as cyclin D1. This novel activation of the Wnt pathway by Src most probably contributes to the oncogenic phenotype of cancer cells.

scholarly journals Eukaryotic initiation factor 6 selectively regulates Wnt signaling and β-catenin protein synthesis

Oncogene ◽  
2007 ◽  
Vol 27 (6) ◽  
pp. 755-762 ◽  
Author(s):  
Y Ji ◽  
S Shah ◽  
K Soanes ◽  
M N Islam ◽  
B Hoxter ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Wnt Signaling ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor

scholarly journals Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification

2020 ◽  
Author(s):  
Alice H. Reis ◽  
Sergei Y. Sokol
Keyword(s):  
Wnt Signaling ◽  
Target Genes ◽  
Gene Activation ◽  
Inhibitory Effect ◽  
T Cell Factor ◽  
Anteroposterior Axis ◽  
Axis Specification ◽  
Wnt Ligands ◽  
Context Specific ◽  
Transcriptional Complex

SummaryThe Wnt pathway activates target genes by controlling the β-catenin-T-cell factor (TCF) transcriptional complex during embryonic development and cancer. This pathway can be potentiated by R-spondins, a family of proteins that bind RNF43/ZNRF3 E3 ubiquitin ligases and LGR4/5 receptors to prevent Frizzled degradation. Here we demonstrate that, during Xenopus anteroposterior axis specification, Rspo2 functions as a Wnt antagonist, both morphologically and at the level of gene targets and pathway mediators. Unexpectedly, the binding to RNF43/ZNRF3 and LGR4/5 was not required for the Wnt inhibitory activity. Moreover, Rspo2 did not influence Dishevelled phosphorylation in response to Wnt ligands, suggesting that Frizzled activity is not affected. Further analysis indicated that the Wnt antagonism is due to the inhibitory effect of Rspo2 on TCF3/TCF7L1 phosphorylation that normally leads to target gene activation. Consistent with this mechanism, Rspo2 anteriorizing activity has been rescued in TCF3-depleted embryos. These observations suggest that Rspo2 is a context-specific regulator of TCF3 phosphorylation and Wnt signaling.

scholarly journals Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin

2019 ◽  
Author(s):  
Alin Vonica ◽  
Neha Bhat ◽  
Keith Phan ◽  
Jinbai Guo ◽  
Lăcrimioara Iancu ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Bmp Signaling ◽  
Protein Domain ◽  
Axis Formation ◽  
Intercellular Signaling ◽  
Functional Protein ◽  
Animal Development ◽  
Bmp Receptors ◽  
Wnt Inhibitor

AbstractAnimal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1 is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebrafish, and chicken. It encodes a bi-functional protein with a novel protein domain that can bind to Wnt and BMP receptors and block downstream signaling.

Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3462-3469 ◽  
Author(s):  
José Román-Gómez ◽  
Lucia Cordeu ◽  
Xabier Agirre ◽  
Antonio Jiménez-Velasco ◽  
Edurne San José-Eneriz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
Disease Free Survival ◽  
Wnt Inhibitor ◽  
Wnt Inhibitors

Abstract Activation of the Wnt/β-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/β-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of β-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2′-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).

scholarly journals Double abdomen in a short-germ insect: Zygotic control of axis formation revealed in the beetle Tribolium castaneum

2018 ◽  
Vol 115 (8) ◽  
pp. 1819-1824 ◽  
Author(s):  
Salim Ansari ◽  
Nicole Troelenberg ◽  
Van Anh Dao ◽  
Tobias Richter ◽  
Gregor Bucher ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Germ Cell ◽  
Wnt Signaling ◽  
Tribolium Castaneum ◽  
Target Genes ◽  
Growth Zone ◽  
Axis Formation ◽  
Segmentation Clock ◽  
Second Growth ◽  
Zygotic Control

The distinction of anterior versus posterior is a crucial first step in animal embryogenesis. In the fly Drosophila, this axis is established by morphogenetic gradients contributed by the mother that regulate zygotic target genes. This principle has been considered to hold true for insects in general but is fundamentally different from vertebrates, where zygotic genes and Wnt signaling are required. We investigated symmetry breaking in the beetle Tribolium castaneum, which among insects represents the more ancestral short-germ embryogenesis. We found that maternal Tc-germ cell-less is required for anterior localization of maternal Tc-axin, which represses Wnt signaling and promotes expression of anterior zygotic genes. Both RNAi targeting Tc-germ cell-less or double RNAi knocking down the zygotic genes Tc-homeobrain and Tc-zen1 led to the formation of a second growth zone at the anterior, which resulted in double-abdomen phenotypes. Conversely, interfering with two posterior factors, Tc-caudal and Wnt, caused double-anterior phenotypes. These findings reveal that maternal and zygotic mechanisms, including Wnt signaling, are required for establishing embryo polarity and induce the segmentation clock in a short-germ insect.

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