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.

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.

Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway

Development ◽  
2000 ◽  
Vol 127 (10) ◽  
pp. 2227-2238 ◽  
Author(s):  
M. Tada ◽  
J.C. Smith
Keyword(s):  
Wnt Pathway ◽  
Target Genes ◽  
Dominant Negative ◽  
Beta Catenin ◽  
Transcription Activator ◽  
Amphibian Embryo ◽  
Morphogenetic Movements ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt

Gastrulation in the amphibian embryo is driven by cells of the mesoderm. One of the genes that confers mesodermal identity in Xenopus is Brachyury (Xbra), which is required for normal gastrulation movements and ultimately for posterior mesoderm and notochord differentiation in the development of all vertebrates. Xbra is a transcription activator, and interference with transcription activation leads to an inhibition of morphogenetic movements during gastrulation. To understand this process, we have screened for downstream target genes of Brachyury (Tada, M., Casey, E., Fairclough, L. and Smith, J. C. (1998) Development 125, 3997–4006). This approach has now allowed us to isolate Xwnt11, whose expression pattern is almost identical to that of Xbra at gastrula and early neurula stages. Activation of Xwnt11 is induced in an immediate-early fashion by Xbra and its expression in vivo is abolished by a dominant-interfering form of Xbra, Xbra-En(R). Overexpression of a dominant-negative form of Xwnt11, like overexpression of Xbra-En(R), inhibits convergent extension movements. This inhibition can be rescued by Dsh, a component of the Wnt signalling pathway and also by a truncated form of Dsh which cannot signal through the canonical Wnt pathway involving GSK-3 and (beta)-catenin. Together, our results suggest that the regulation of morphogenetic movements by Xwnt11 occurs through a pathway similar to that involved in planar polarity signalling in Drosophila.

scholarly journals Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e101894 ◽  
Author(s):  
Fan Hu ◽  
Li Xu ◽  
Zhi-Hua Liu ◽  
Meng-Meng Ge ◽  
Di-Yun Ruan ◽  
...  
Keyword(s):  
Lead Exposure ◽  
Wnt Pathway ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt

scholarly journals Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation

2003 ◽  
Vol 162 (5) ◽  
pp. 899-908 ◽  
Author(s):  
Lilia Topol ◽  
Xueyuan Jiang ◽  
Hosoon Choi ◽  
Lisa Garrett-Beal ◽  
Peter J. Carolan ◽  
...  
Keyword(s):  
Limb Development ◽  
Wnt Pathway ◽  
Biological Systems ◽  
Signaling Molecules ◽  
Tumor Formation ◽  
Canonical Wnt Pathway ◽  
Noncanonical Pathway ◽  
Canonical Wnt

Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing β-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of β-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and β-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote β-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.

Neonatal growth and regeneration of β-cells are regulated by the Wnt/β-catenin signaling in normal and diabetic rats

2010 ◽  
Vol 298 (2) ◽  
pp. E245-E256 ◽  
Author(s):  
Florence Figeac ◽  
Benjamin Uzan ◽  
Monique Faro ◽  
Noura Chelali ◽  
Bernard Portha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Pathway ◽  
Diabetic Rats ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Gsk 3Β ◽  
Canonical Wnt

Wnt/β-catenin signaling is critical for a variety of fundamental cellular processes. Here, we investigated the implication of the Wnt/β-catenin signaling in the in vivo regulation of β-cell growth and regeneration in normal and diabetic rats. To this aim, TCF7L2, the distal effector of the canonical Wnt pathway, was knocked down in groups of normal and diabetic rats by the use of specific antisense morpholino-oligonucleotides. In other groups of diabetic rats, the Wnt/β-catenin pathway was activated by the inhibition of its negative regulator GSK-3β. GSK-3β was inactivated by either LiCl or anti-GSK-3β oligonucleotides. The β-cell mass was evaluated by morphometry. β-cell proliferation was assessed in vivo and in vitro by BrdU incorporation method. In vivo β-cell neogenesis was estimated by the evaluation of PDX1-positive ductal cells and GLUT2-positive ductal cells and the number of β cells budding from the ducts. We showed that the in vivo disruption of the canonical Wnt pathway resulted in the alteration of normal and compensatory growth of β-cells mainly through the inhibition of β-cell proliferation. Conversely, activation of the Wnt pathway through the inhibition of GSK-3β had a significant stimulatory effect on β-cell regeneration in diabetic rats. In vitro, GSK-3β inactivation resulted in the stimulation of β-cell proliferation. This was mediated by the stabilization of β-catenin and the induction of cyclin D. Taken together, our results demonstrate the involvement of the canonical Wnt signaling in the neonatal regulation of normal and regenerative growth of pancreatic β-cells. Moreover, we provide evidence that activation of this pathway by pharmacological maneuvers can efficiently improve β-cell regeneration in diabetic rats. These findings might have potential clinical applications in the regenerative therapy of diabetes.

scholarly journals Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner

Oncogene ◽  
2008 ◽  
Vol 27 (25) ◽  
pp. 3546-3555 ◽  
Author(s):  
M Caspi ◽  
A Zilberberg ◽  
H Eldar-Finkelman ◽  
R Rosin-Arbesfeld
Keyword(s):  
Wnt Signalling ◽  
Signalling Pathway ◽  
Independent Manner ◽  
Wnt Signalling Pathway ◽  
Gsk 3Β ◽  
Canonical Wnt

scholarly journals Efficiency of Cell Therapy to GC-Induced ONFH: BMSCs with Dkk-1 Interference Is Not Superior to Unmodified BMSCs

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Zhun ◽  
Li Donghai ◽  
Yang Zhouyuan ◽  
Zhao Haiyan ◽  
Kang Pengde
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Therapy ◽  
Wnt Pathway ◽  
Allograft Bone ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt ◽  
Dickkopf 1

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a hip disorder, and it threatens patients who require megadose of steroid therapies. Nowadays, no valid therapies can reverse the development of GC-induced ONFH once it occurs. Stem cell therapy to GC-induced ONFH would be a promising choice. Although the pathogenesis of GC-induced ONFH is not yet fully clear, Dickkopf-1 (Dkk-1) upregulated by excessive GC use, which hinders the canonical Wnt pathway, could be an explanation. Thus, the aim of the present work lies in investigating the efficiency of the allograft bone marrow stem cells (BMSCs) with Dkk-1 interference in preventing the progression of the GC-induced ONFH. Lentivirus-meditated Dkk-1 RNAi was introduced into BMSCs which was exposed to dexamethasone (10−6 mol/L) in vitro. This interference blocked Dkk-1 overexpression by GC and afterwards prompted the transduction of Wnt/β-catenin in which the Runx2 and PPARγ were upregulated and downregulated, respectively. Thus, the osteogenesis was promoted while adipogenesis was inhibited. In vivo, GC-induced ONFH rats were treated by allotransplantation of BMSCs with Dkk-1 interference, and the progression of the disease was prevented. However, the effects were not significantly superior to treatment with nongenetically modified or normal BMSCs.

scholarly journals A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells

2020 ◽  
Author(s):  
Qiuyu Guo ◽  
Albert Kim ◽  
Bin Li ◽  
Andrew Ransick ◽  
Helena Bugacov ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Wnt Pathway ◽  
Target Genes ◽  
De Novo ◽  
Feedback Regulation ◽  
Canonical Wnt Pathway ◽  
Dependent Cell ◽  
Nephron Progenitor ◽  
Canonical Wnt ◽  
Gsk3 Inhibitor

AbstractThe canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is independent of direct engagement of TCF/LEF/ β-catenin transcriptional complexes at low-CHIR dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin’s direct transcriptional role is restricted to the induction of NPCs where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.

scholarly journals Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish

2020 ◽  
Author(s):  
Lucy M. McGowan ◽  
Erika Kague ◽  
Alistair Vorster ◽  
Elis Newham ◽  
Stephen Cross ◽  
...  
Keyword(s):  
Bone Repair ◽  
Bone Matrix ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Matrix Deposition ◽  
Wnt Signalling Pathway ◽  
Canonical Wnt

SummaryBone homeostasis is a dynamic, multicellular process which is required throughout life to maintain bone integrity, prevent fracture and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in humans, as well as functional haematopoiesis of leukocytes in vivo, but the mechanisms by which it promotes bone health and repair are not fully understood. We used CRISPR-Cas9 to generate mutant zebrafish lacking Wnt16 (wnt16-/-) to study its effect on bone dynamically. wnt16 mutants displayed variable tissue mineral density and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16-/- and wild type (WT) zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell-dynamics in vivo. wnt16 mutants repaired fractures more slowly compared to WT zebrafish. Osteoblast cell number was reduced at the fracture site 4 days post-injury in wnt16 mutants, coinciding with prolonged activation of the canonical Wnt signalling pathway. Surprisingly, we found no evidence that the recruitment of innate immune cells to fractures was altered in wnt16 mutants. This study highlights zebrafish as an emerging model for functionally validating osteoporosis-associated genes and investigating fracture repair dynamically in vivo. Using this model, we demonstrate that Wnt16 protects against fracture and is likely to support bone repair by attenuating the activation of the canonical Wnt signalling pathway to facilitate osteoblast recruitment and bone matrix deposition.

scholarly journals A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Qiuyu Guo ◽  
Albert D Kim ◽  
Bin Li ◽  
Andrew Ransick ◽  
Helena Bugacov ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Wnt Pathway ◽  
Target Genes ◽  
De Novo ◽  
Feedback Regulation ◽  
Canonical Wnt Pathway ◽  
Dependent Cell ◽  
Nephron Progenitor ◽  
Canonical Wnt ◽  
Gsk3 Inhibitor

The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin's direct transcriptional role is restricted to the induction of NPCs where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.

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