Wingless and its signalling pathway have common and separable functions during tracheal development

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4407-4417 ◽  
Author(s):  
M. Llimargas
Keyword(s):  
Gene Product ◽  
Respiratory System ◽  
Wnt Pathway ◽  
Target Genes ◽  
Wnt Signalling ◽  
Canonical Pathway ◽  
Signalling Pathway ◽  
Dorsoventral Axis ◽  
Separable Functions ◽  
Antagonistic Interactions

The Drosophila tracheal tree consists of a tubular network of epithelial branches that constitutes the respiratory system. Groups of tracheal cells migrate towards stereotyped directions while they acquire specific tracheal fates. This work shows that the wingless/WNT signalling pathway is needed within the tracheal cells for the formation of the dorsal trunk and for fusion of the branches. These functions are achieved through the regulation of target genes, such as spalt in the dorsal trunk and escargot in the fusion cells. The pathway also aids tracheal invagination and helps guide the ganglionic branch. Moreover the wingless/WNT pathway displays antagonistic interactions with the DPP (decapentaplegic) pathway, which regulates branching along the dorsoventral axis. Remarkably, the wingless gene itself, acting through its canonical pathway, seems not to be absolutely required for all these tracheal functions. However, the artificial overexpression of wingless in tracheal cells mimics the overexpression of a constitutively activated armadillo protein. The results suggest that another gene product, possibly a WNT, could help to trigger the wingless cascade in the developing tracheae.

Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo

2015 ◽  
Vol 466 (2) ◽  
pp. 415-430 ◽  
Author(s):  
Cheril Tapia-Rojas ◽  
Andreas Schüller ◽  
Carolina B. Lindsay ◽  
Roxana C. Ureta ◽  
Cristóbal Mejías-Reyes ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Wnt Pathway ◽  
Target Genes ◽  
Competitive Inhibition ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Canonical Wnt Pathway ◽  
Gsk 3Β ◽  
Canonical Wnt

Andrographolide activates the canonical Wnt pathway and induces the transcription of Wnt target genes through a mechanism independent of Wnt ligand binding to its receptor, by direct substrate-competitive inhibition of GSK-3.

scholarly journals Is resistant starch protective against colorectal cancer via modulation of the WNT signalling pathway?

2015 ◽  
Vol 74 (3) ◽  
pp. 282-291 ◽  
Author(s):  
Fiona C. Malcomson ◽  
Naomi D. Willis ◽  
John C. Mathers
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Resistant Starch ◽  
Wnt Pathway ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Wnt Signalling Pathway ◽  
Crypt Cell Proliferation ◽  
And Migration ◽  
Epigenetic Modulation

Epidemiological and experimental evidence suggests that non-digestible carbohydrates (NDC) including resistant starch are protective against colorectal cancer. These anti-neoplastic effects are presumed to result from the production of the SCFA, butyrate, by colonic fermentation, which binds to the G-protein-coupled receptor GPR43 to regulate inflammation and other cancer-related processes. The WNT pathway is central to the maintenance of homeostasis within the large bowel through regulation of processes such as cell proliferation and migration and is frequently aberrantly hyperactivated in colorectal cancers. Abnormal WNT signalling can lead to irregular crypt cell proliferation that favours a hyperproliferative state. Butyrate has been shown to modulate the WNT pathway positively, affecting functional outcomes such as apoptosis and proliferation. Butyrate's ability to regulate gene expression results from epigenetic mechanisms, including its role as a histone deacetylase inhibitor and through modulating DNA methylation and the expression of microRNA. We conclude that genetic and epigenetic modulation of the WNT signalling pathway may be an important mechanism through which butyrate from fermentation of resistant starch and other NDC exert their chemoprotective effects.

Investigations of dynamic amyloid-like structures of the Wnt signalling pathway by solid-state NMR

2018 ◽  
Vol 54 (32) ◽  
pp. 3959-3962 ◽  
Author(s):  
M. E. Ward ◽  
M. A. Daniëls ◽  
E. C. van Kappel ◽  
M. M. Maurice ◽  
M. Baldus
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Solid State ◽  
Magnetic Resonance ◽  
Solid State Nmr ◽  
Wnt Pathway ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Wnt Signalling Pathway ◽  
Structural Details ◽  
Nuclear Magnetic

Solid-state nuclear magnetic resonance can reveal native structural details of amyloid-like signalling proteins of the Wnt pathway.

scholarly journals Methane Saline Ameliorates Traumatic Brain Injury through Anti-Inflammatory, Antiapoptotic, and Antioxidative Effects by Activating the Wnt Signalling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Meng Li ◽  
Weiman Gao ◽  
Le Ji ◽  
Jia Li ◽  
Wanting Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Wnt Pathway ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Sprague Dawley ◽  
Wnt Signalling Pathway ◽  
Sprague Dawley Rats ◽  
Antioxidative Effects ◽  
Anti Inflammatory

Objective. Methane saline (MS) can be used to treat many diseases via its anti-inflammatory, antiapoptotic, and antioxidative activities. However, to date, there is no published evidence as to whether MS has any effect on traumatic brain injury (TBI). The Wnt signalling pathway regulates cell proliferation, differentiation, migration, and apoptosis; however, whether the Wnt signalling pathway regulates any effect of MS on TBI is unknown. This study was designed to explore the role of MS in the treatment of TBI and whether the Wnt pathway is involved. Methods. Sprague-Dawley rats were randomly divided into five groups: sham, TBI, TBI+10 ml/kg MS, TBI+20 ml/kg MS, and TBI+30 ml/kg MS. After induction of TBI, MS was injected intraperitoneally once daily for seven consecutive days. Neurological function was evaluated by the Neurological Severity Score (NSS) at 1, 7, and 14 days after TBI. Haematoxylin-eosin (HE) staining, inflammatory factors, neuron-specific enolase (NSE) staining, oxidative stress, and cell apoptosis were measured and compared 14 d after TBI to identify the optimal dose of MS and to investigate the effect of MS on TBI. In the second experiment, Sprague-Dawley rats were randomly divided into four groups: sham, TBI, TBI+20 ml/kg MS, and TBI+20 ml/kg MS+Dickkopf-1 (DKK-1, a specific inhibitor of the Wnt pathway). NSE, caspase-3, superoxide dismutase (SOD), Wnt3a, and β-catenin were detected by real-time PCR and Western blotting. The results from each group were compared 14 d after TBI to determine the regulatory role of the Wnt pathway. Results. Methane saline significantly inhibited inflammation, oxidative stress, and cell apoptosis, thus protecting neurons within 14 days of TBI. The best treatment effect against TBI was obtained with 20 ml/kg MS. When the Wnt pathway was inhibited, the treatment effect of MS was impaired. Conclusion. Methane saline ameliorates TBI through its anti-inflammatory, antiapoptotic, and antioxidative effects via activation of the Wnt signalling pathway, which plays a part but is not the only mechanism underlying the effects of MS. Thus, MS may be a novel strategy for treating TBI.

The homeobox gene Siamois is a target of the Wnt dorsalisation pathway and triggers organiser activity in the absence of mesoderm

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3055-3065 ◽  
Author(s):  
G. Carnac ◽  
L. Kodjabachian ◽  
J.B. Gurdon ◽  
P. Lemaire
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Homeobox Gene ◽  
Neural Tissue ◽  
Wnt Signalling ◽  
Cement Gland ◽  
Signalling Pathway ◽  
Mesoderm Induction ◽  
Embryonic Cells ◽  
Dorsal Mesoderm

Siamois, a Xenopus zygotic homeobox gene with strong dorsalising activity, is expressed in the dorsal-vegetal organiser known as the Nieuwkoop centre. We show that, in contrast to Spemann organiser genes such as goosecoid, chordin and noggin, Siamois gene expression is not induced following overexpression of mesoderm inducers in ectodermal (animal cap) cells. However, Siamois is induced by overexpressing a dorsalising Wnt molecule. Furthermore, like Wnt, Siamois can dorsalise ventral mesoderm and cooperate with Xbrachyury to generate dorsal mesoderm. These results suggest that Siamois is a mediator of the Wnt-signalling pathway and that the synergy between the Wnt and mesoderm induction pathways occurs downstream of the early target genes of these two pathways. Overexpression of Siamois in animal cap cells reveals that this gene can act in a non vegetal or mesodermal context. We show the following. (1) Animal cap cells overexpressing Siamois secrete a factor able to dorsalise ventral gastrula mesoderm in tissue combination experiments. (2) The Spemann organiser-specific genes goosecoid, Xnr-3 and chordin, but not Xlim.1, are activated in these caps while the ventralising gene Bmp-4 is repressed. However, the dorsalising activity of Siamois-expressing animal caps is significantly different from that of noggin- or chordin-expressing animal caps, suggesting the existence of other dorsalising signals in the embryo. (3) Ectodermal cells overexpressing Siamois secrete a neuralising signal and can differentiate into cement gland and, to a lesser extent, into neural tissue. Hence, in the absence of mesoderm induction, overexpression of Siamois is sufficient to confer organiser properties on embryonic cells.

Molecular Docking Studies to Evaluate Small Molecule Inhibitors of Wnt/Betacatenin Signaling Pathway

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Sankari Dantu Sai Shyama Lakshmi ◽  
Maka Sai Sailaja ◽  
Dalal Swetha ◽  
Chanda Chandrasekhar ◽  
Aluru Ranganadha Reddy
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Hydrogen Bonds ◽  
Wnt Pathway ◽  
Docking Studies ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Wnt Signalling Pathway ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt

Canonical Wnt pathway or β catenin dependent pathway is one of the highly conserved signalling pathway which can control gene expression and regulate cell proliferation, cell adhesion, cell migration, cell polarity and organogenesis. Abnormal regulation of β catenin in the canonical wnt signalling pathway leads to transcription of several genes involved in oncogenic programs. Aberrant signalling of the canonical wnt pathway was observed in several types of cancers including hepatocarcinoma, colorectal cancer and lung cancer. Many small molecules were observed to have the potential to block the aberrant wnt signalling pathway by allosteric binding and inhibiting β catenin molecule. The current study involves screening for ligands which can have strong allosteric binds to β catenin and inhibit wnt signalling pathway. Molecular docking studies were used to evaluate the binding capacity of the selected ligands. Curcumin, Cardamonin, FH535 and ICRT-3 were used as ligands for the molecular docking study with β catenin binding Transcription factor -4 receptor. All chosen ligands have exhibited significant binding energies with the receptor. The highest -9.518272 kcal/mol with Cardamonin followed by -9.28359 kcal/mol with FH535, -8.422604 kcal/mol with curcumin and the least -8.407231 kcal/mol with ICRT-3. All the ligands showed at least 1 hydrogen bond with the target receptor whereas Cardamonin showed 3 hydrogen bonds. Curcumin is a close second forming 2 hydrogen bonds while FH535 and ICRT-3 form only 1 hydrogen bond. The 2D interactions of the ligand and the molecule are visualised by using chimera. We observed Cardamonin to have a very strong binding affinity with the target receptor. Cardamonin can be a suitable drug candidate and might have the potential to inhibit the β catenin dependent wnt signalling pathway.

Epigenetic Regulation of the WNT Canonical Pathway in Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3340-3340
Author(s):  
Anthea C Peters ◽  
Randy Chung ◽  
Charles S Wong ◽  
Leah C Young ◽  
Tony Reiman ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Promoter Methylation ◽  
Wnt Pathway ◽  
Cell Lymphoma ◽  
Glycogen Synthase ◽  
Wnt Signalling ◽  
Canonical Pathway ◽  
Receptor Interaction ◽  
Mantle Cell ◽  
Gsk 3Β

Abstract Dysregulation of the WNT signalling pathway is an important event in the pathogenesis of several types of cancer, including colon cancer and acute leukemia. When a WNT protein binds to its receptor, glycogen synthase kinase (GSK)-3β is inactivated by phosphorylation (i.e. pGSK-3β) allowing β-catenin to accumulate in the nucleus and promote transcription of proliferative genes. Conversely, a protein complex that includes GSK-3β initiates destruction of β-catenin if no WNT protein binds its receptor or if an antagonist interferes with WNT ligand-receptor interaction. We previously demonstrated that the WNT canonical pathway is often constitutively active in mantle cell lymphoma (MCL), a subtype of B-cell non-Hodgkin lymphoma. We showed that GSK-3β is phosphorylated, thus inactive, in two-thirds of MCL cases, and that a high level of pGSK-3β correlates with both β-catenin expression and poor patient survival. In order to elucidate the mechanisms of constitutive WNT signalling in MCL, we investigated the RNA expression of six WNT pathway antagonists including WIF-1 using fresh tumour samples and three types of cultured MCL cells. In vivo WIF-1 expression was abundant only in tumours shown to lack pGSK-3β expression. We also examined the regulation of these WNT antagonists by promoter methylation by treating cultured cells with demethylating agent 5-aza-2’-deoxycytidine. The WNT pathway inhibitors were often negatively regulated in MCL-derived cell lines by epigenetic DNA methylation; inhibitors that were not expressed at baseline showed expression after demethylation treatment in at least one MCL cell line. Methylation-specific PCR confirmed that the promoter region of WIF-1 was methylated in almost half of MCL tumour samples. Our data demonstrates that in MCL several antagonists of the canonical WNT pathway are negatively regulated by promoter methylation, thereby allowing aberrant WNT pathway activation. This data confirms that WNT signalling is important in MCL pathogenesis, and identifies potential therapeutic targets for MCL.

MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway

2010 ◽  
Vol 391 (2/3) ◽  
Author(s):  
Ser Sue Ng ◽  
Tokameh Mahmoudi ◽  
Vivian S.W. Li ◽  
Pantelis Hatzis ◽  
Paul J. Boersema ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Endogenous Gene ◽  
Wnt Signalling Pathway ◽  
Mitogen Activated Protein ◽  
Canonical Wnt

Abstract A central point of regulation in the Wnt/β-catenin signalling pathway is the formation of the β-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of β-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/β-catenin pathway. These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH2-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes.

scholarly journals Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma

2018 ◽  
Vol 47 (5) ◽  
pp. 1819-1834 ◽  
Author(s):  
Hor-Yue Tan ◽  
Ning Wang ◽  
Sha Li ◽  
Ming Hong ◽  
Wei Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Immunoprecipitation ◽  
Wnt Pathway ◽  
Target Genes ◽  
Binding Capacity ◽  
Mangifera Indica ◽  
Inhibitory Effect ◽  
Wnt Signalling ◽  
Cellular Models ◽  
Hcc Cells

Background/Aims: The development of hepatocellular carcinoma (HCC) is a complex process which involves deregulation of multiple signalling pathways. The hyper-activation of Wnt signalling promotes sustained expansion, invasion, and neovascularization of HCC. Mangiferin, a natural small molecule present in Mangifera indica L. has been shown to inactivate β-catenin, which is an indispensable regulator in Wnt pathway. Our study aimed to determine whether mangiferin has any inhibitory effect on HCC and examine how it modulates Wnt signalling. Methods: The tumour inhibitory effect of mangiferin was examined by in vitro cellular models and an in vivo orthotopic HCC implantation model. The genes responsible for mangiferin-mediated anti-HCC were delineated by polymerase chain reaction (PCR) microarray. The expression of target genes was further determined by quantitative PCR and immuno-blotting assays. The binding capacity of Wilms’ tumour 1 (WT1) to the lymphoid enhancer-binding factor 1 (LEF1) promoter was confirmed by chromatin immunoprecipitation-qPCR. Results: Oral administration of mangiferin inhibited orthotopic tumour growth. Cellular investigations confirmed the dose-dependent inhibition of mangiferin on HCC expansion and invasion. PCR array combined with Gene Ontology analysis revealed that the Wnt pathway was the predominant target of mangiferin and LEF1 was the most reduced gene in the Wnt pathway. Overexpression of LEF1 diminished repression of Wnt signalling and reduced proliferation activity in mangiferin-treated HCC cells. The mangiferin-mediated down-regulation of LEF1 was independent of β-catenin but associated with WT1 protein. WT1 knock-in in HCC cells further enhanced LEF1 expression. Chromatin immunoprecipitation assays revealed that the mangiferin induced repression of LEF1 was associated with decreased occupancy of WT1 on the LEF1 promoter. Conclusion: Our study identifies a novel mechanism of hepatocellular carcinoma inhibition through β-catenin-independent Wnt signalling, which is regulated by WT1-associated LEF1 repression. The study also highlights mangiferin as a promising Wnt inhibitor for HCC treatment.

Azacytidine and Gemtuzumab Ozogamicin Co-Operate to Inhibit the Wnt Pathway and Increase Cytotoxicity in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2991-2991 ◽  
Author(s):  
Mays Jawad ◽  
Nigel H. Russell ◽  
Monica Pallis
Keyword(s):  
Cell Survival ◽  
Cell Fate ◽  
Wnt Pathway ◽  
Target Genes ◽  
Wnt Signaling Pathway ◽  
Gemtuzumab Ozogamicin ◽  
Wnt Signalling ◽  
Beta Catenin ◽  
Cell Kill ◽  
The Difference

Abstract Thirty percent of acute myeloid leukaemia (AML) patients contain somatic mutations (internal tandem duplications-ITD) of FLT3 gene (FLT3/ITD) that are associated with poor prognosis. We have previously shown that Gemtuzumab Ozogamicin (Mylotarg), the CD33 calichaemicin-conjugate, targets the leukaemic stem and progenitor cells (LSPC) of FLT3/ITD samples better than WT samples (ASH 2007, Abstract #650). The Wnt signalling pathway has a role in the pathogenesis of AML, particularly in cells capable of self renewal, i.e. LSPC. Beta-catenin is one downstream effector of Wnt signalling, which upon stimulation will activate transcription of target genes, particularly oncogenes such as c-myc and cyclin D1, that influence cell proliferation, survival and cell fate. More recently, a synergistic effect on activation of Wnt signaling pathway in leukaemic transformation by FLT3/ITD has been shown, suggesting that beta-catenin induction may be one transforming event in AML achieved by FLT3/ITD activation. Therefore, identifying therapeutic agents that specifically target the Wnt pathway at various positions may be necessary for complete inhibition of this pathway in AML. In haemopoietic cells, treatment with the hypomethylating agent 5′-Azacytidine (Aza) results in progressive demethylation of previously methylated Wnt inhibitors and re-expression of transcripts and downregulation of Wnt signalling. The aim of this study is to investigate whether Aza targets the Wnt pathway in AML, whether the combination with Mylotarg further frustrates this pathway leading to cell death and whether this is more pronounced in FLT3/ITD samples. We examined cell survival in the presence of Aza, Mylotarg or the combination in FLT3/WT (HL60 and U937) and FLT3/ITD (MOLM13 and MV4-11) cell lines. Both single Aza and Mylotarg 48hr treatment resulted in significant cell kill (30–42% and 51–74%, respectively), whereas this effect was enhanced (additive) when the Aza/Mylotarg combination was used (69–85% cell kill). Although slightly more sensitive in FLT3/ITD cells (76–85% cell kill), our data indicate that the Aza/Mylotarg combination is effective even in FLT3/WT cells (69–71% cell kill). In order to assess possible mechanism of action, beta-catenin levels were measured in these treated cells. Reduction in beta-catenin levels was similar in Aza-treated FLT3/ITD and WT cells (7–23% and 9–13%, respectively). In contrast, Mylotarg and Aza/Mylotarg combination resulted in a significant beta-catenin reduction in FLT3/ITD cells compared to WT cells: 41–47% in FLT3/ITD and 0–16% in FLT3/WT for Mylotarg and 52–59% in FLT3/ITD and 0–17% in FLT3/WT for Aza/Mylotarg combination. The FLT3 inhibitor AG1296 also downregulated beta-catenin levels in MV4-11 cells, suggesting that Mylotarg may in fact be targeting the Wnt pathway by inhibiting FLT3 signalling. We have also compared cell survival in FLT3/ITD and compared them to FLT3/WT in LSPC from primary AMLs. CD34+CD38−CD123+ LSPC from FLT3/ITD samples were more sensitive to Aza compared to LSPC of FLT3/WT samples (15% vs 42% cell kill, respectively; n=3, 72hrs). The difference is enhanced when the Mylotarg/Aza combination is used (23% vs 61% cell kill in FLT3/WT and FLT3/ITD, respectively). We conclude that the Mylotarg/Aza combination effectively inhibits the Wnt pathway and targets LSPCs in AML.

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