Статті в журналах: "Wnt System"

1

Staal, Frank J. T., Tiago C. Luis, and Machteld M. Tiemessen. "WNT signalling in the immune system: WNT is spreading its wings." Nature Reviews Immunology 8, no. 8 (August 2008): 581–93. http://dx.doi.org/10.1038/nri2360.

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2

Staal, Frank J. T., Tiago C. Luis, and Machteld M. Tiemessen. "Erratum: WNT signalling in the immune system: WNT is spreading its wings." Nature Reviews Immunology 15, no. 5 (April 7, 2015): 329. http://dx.doi.org/10.1038/nri3847.

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3

Park, Min Hee, Eun-Ah Sung, Margot Sell, and Wook-Jin Chae. "Dickkopf1: An Immunomodulator in Tissue Injury, Inflammation, and Repair." ImmunoHorizons 5, no. 11 (November 1, 2021): 898–908. http://dx.doi.org/10.4049/immunohorizons.2100015.

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Abstract Upon injury, inflammation and repair processes are orchestrated to maintain tissue homeostasis. The Wnt ligands play essential roles in cell differentiation and proliferation for tissue repair and regeneration. It is increasingly clear that Wnt ligands play crucial immune-modulatory roles in inflammatory diseases. It is predicted that comprehensive research regarding the cross-talk between nonimmune and immune cells in tissue injury and repair will flourish. The Wnt system and immune system interaction will be critical to understanding tissue injury, inflammation, and repair. In this study, we will first introduce the Wnt system and review the role of the Wnt system in tissue regeneration and repair. We will review the previous literature regarding how the Wnt ligands regulate the immune system. Next, we will discuss the current and future perspectives of Wnt ligands to target cancer and other immunological diseases. Finally, we will discuss the quintessential Wnt antagonist Dickkopf1 as an immunomodulatory ligand.

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4

Whangbo, J., J. Harris, and C. Kenyon. "Multiple levels of regulation specify the polarity of an asymmetric cell division in C. elegans." Development 127, no. 21 (November 1, 2000): 4587–98. http://dx.doi.org/10.1242/dev.127.21.4587.

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Wnt signaling systems play important roles in the generation of cell and tissue polarity during development. We describe a Wnt signaling system that acts in a new way to orient the polarity of an epidermal cell division in C. elegans. In this system, the EGL-20/Wnt signal acts in a permissive fashion to polarize the asymmetric division of a cell called V5. EGL-20 regulates this polarization by counteracting lateral signals from neighboring cells that would otherwise reverse the polarity of the V5 cell division. Our findings indicate that this lateral signaling pathway also involves Wnt pathway components. Overexpression of EGL-20 disrupts both the asymmetry and polarity of lateral epidermal cell divisions all along the anteroposterior (A/P) body axis. Together our findings suggest that multiple, inter-related Wnt signaling systems may act together to polarize asymmetric cell divisions in this tissue.

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5

Bordonaro, Michael. "Modular Cre/lox System and Genetic Therapeutics for Colorectal Cancer." Journal of Biomedicine and Biotechnology 2009 (2009): 1–12. http://dx.doi.org/10.1155/2009/358230.

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The Cre/lox system is a powerful tool for targeting therapeutic effectors in a wide variety of human disorders. I review a Cre/lox Wnt-targeted system that has shown promise against Wnt-positive colorectal cancer cell lines. In addition to Wnt-specific targeting of cell death inducers, the modular nature of this gene therapy model system can be exploited by designing positive and negative feedback loops to either amplify or inhibit Wnt activity for experimental or therapeutic benefit. I discuss the structural components and performance parameters of the system, the implication of these findings with respect to cancer stem cells, as well as the general applicability of this system to any disorder characterized by differential gene expression. I also consider the issue of gene delivery as well as in vivo testing requirements necessary for the further characterization and development of this system.

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6

Hollyday, Margaret, Jill A. McMahon, and Andrew P. McMahon. "Wnt expression patterns in chick embryo nervous system." Mechanisms of Development 52, no. 1 (July 1995): 9–25. http://dx.doi.org/10.1016/0925-4773(95)00385-e.

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7

Hrckulak, Dusan, Lucie Janeckova, Lucie Lanikova, Vitezslav Kriz, Monika Horazna, Olga Babosova, Martina Vojtechova, Katerina Galuskova, Eva Sloncova, and Vladimir Korinek. "Wnt Effector TCF4 Is Dispensable for Wnt Signaling in Human Cancer Cells." Genes 9, no. 9 (September 1, 2018): 439. http://dx.doi.org/10.3390/genes9090439.

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T-cell factor 4 (TCF4), together with β-catenin coactivator, functions as the major transcriptional mediator of the canonical wingless/integrated (Wnt) signaling pathway in the intestinal epithelium. The pathway activity is essential for both intestinal homeostasis and tumorigenesis. To date, several mouse models and cellular systems have been used to analyze TCF4 function. However, some findings were conflicting, especially those that were related to the defects observed in the mouse gastrointestinal tract after Tcf4 gene deletion, or to a potential tumor suppressive role of the gene in intestinal cancer cells or tumors. Here, we present the results obtained using a newly generated conditional Tcf4 allele that allows inactivation of all potential Tcf4 isoforms in the mouse tissue or small intestinal and colon organoids. We also employed the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to disrupt the TCF4 gene in human cells. We showed that in adult mice, epithelial expression of Tcf4 is indispensable for cell proliferation and tumor initiation. However, in human cells, the TCF4 role is redundant with the related T-cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) transcription factors.

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8

Dickinson, M. E., R. Krumlauf, and A. P. McMahon. "Evidence for a mitogenic effect of Wnt-1 in the developing mammalian central nervous system." Development 120, no. 6 (June 1, 1994): 1453–71. http://dx.doi.org/10.1242/dev.120.6.1453.

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The analysis of mutant alleles at the Wnt-1 locus has demonstrated that Wnt-1-mediated cell signalling plays a critical role in development of distinct regions of the embryonic central nervous system (CNS). To determine how these signals participate in the formation of the CNS, we have ectopically expressed this factor in the spinal cord under the control of the Hoxb-4 Region A enhancer. Ectopic Wnt-1 expression causes a dramatic increase in the number of cells undergoing mitosis in the ventricular region and a concomitant ventricular expansion. Although this leads to consistent changes in the relative proportions of dorsal and ventral regions, Wnt-1 does not appear to act as a primary patterning signal. Rather, our experiments indicate that Wnt-1 can act as a mitogen in the developing CNS.

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9

Li, Shengchun, Yilin Zhang, Lihao Guo, and Xiaofang Li. "Potential Application of Alternate Tillage (AT) in a Rice–Wheat Rotation System—Based on Soil Physical Properties, Wheat Growth and Yield." Soil Systems 6, no. 3 (September 1, 2022): 70. http://dx.doi.org/10.3390/soilsystems6030070.

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Alternate tillage (AT) has the potential to reduce inputs and improve soil quality and crop yield, but there has been no research on the effect of AT on soil and wheat in a rice–wheat rotation system. In this study, field experiments were conducted to examine the effects of four tillage management methods (conventional tilling (CT) in each crop (RCT–WCT), no tilling (NT) in rice and conventional tilling in wheat (RNT–WCT, AT1), conventional tilling in rice and no tilling in wheat (RCT–WNT, AT2), and no tilling in each crop (RNT–WNT)) on the physical properties of soil, wheat growth, and yield. At the 0–5 cm soil layer, CT in the wheat season increased bulk density (BD) and decreased total properties, but it decreased BD at the 5–40 cm soil layer, and the effect of RCT–WCT was significantly greater than that of RNT–WCT. CT in the wheat season increased the root activity, root dry weight, net photosynthetic rate, leaf area index, antioxidant enzyme activities, and yield, and there was no significant effect between RCT–WCT and RNT–WCT. RNT-WCT has the potential to reduce inputs and maintain wheat yields.

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10

Hu, S., L. Yang, C. Wu, and TC-Y. Liu. "Regulation of Wnt signaling by physical exercise in the cell biological processes of the locomotor system." Physiology International 106, no. 1 (March 2019): 1–20. http://dx.doi.org/10.1556/2060.106.2019.07.

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In the past decade, researches on Wnt signaling in cell biology have made remarkable progress regarding our understanding of embryonic development, bone formation, muscle injury and repair, neurogenesis, and tumorigenesis. The study also showed that physical activity can reverse age-dependent decline in skeletal muscle, preventing osteoporosis, regenerative neurogenesis, hippocampal function, cognitive ability, and neuromuscular junction formation, and the age-dependent recession is highly correlated with Wnt signaling pathways. However, how the biological processes in cell and physical activity during/following exercise affect the Wnt signaling path of the locomotor system is largely unknown. In this study, we first briefly introduce the important features of the cellular biological processes of exercise in the locomotor system. Then, we discuss Wnt signaling and review the very few studies that have examined Wnt signaling pathways in cellular biological processes of the locomotor system during physical exercise.

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11

Drewes, Lester R. "Frizzled Fissure to Improve Central Nervous System Drug Delivery?" Journal of Cerebral Blood Flow & Metabolism 34, no. 8 (June 4, 2014): 1257. http://dx.doi.org/10.1038/jcbfm.2014.98.

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Delivery of therapeutics to the brain is challenging because of efflux pumps located in the vascular endothelium. A detailed analysis of Wnt signaling in a human brain endothelial cell line indicates that expression and function of P-glycoprotein, a major efflux transporter, is controlled by non-canonical Wnt signaling. Inhibition of this pathway leads to downregulation of P-glycoprotein and increased transcellular drug transport and reveals a potential strategy for improving drug delivery for treatment of neurologic diseases.

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12

Lerner, U. H., and C. Ohlsson. "The WNT system: background and its role in bone." Journal of Internal Medicine 277, no. 6 (May 25, 2015): 630–49. http://dx.doi.org/10.1111/joim.12368.

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13

Lambert, Catherine, Pedro Cisternas, and Nibaldo C. Inestrosa. "Role of Wnt Signaling in Central Nervous System Injury." Molecular Neurobiology 53, no. 4 (May 15, 2015): 2297–311. http://dx.doi.org/10.1007/s12035-015-9138-x.

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14

Gueniot, Florian, Sebastien Rubin, Pauline Bougaran, Alice Abelanet, Jean Luc Morel, Bruno Bontempi, Carole Proust, Pascale Dufourcq, Thierry Couffinhal, and Cecile Duplàa. "Targeting Pdzrn3 maintains adult blood-brain barrier and central nervous system homeostasis." Journal of Cerebral Blood Flow & Metabolism 42, no. 4 (October 13, 2021): 613–29. http://dx.doi.org/10.1177/0271678x211048981.

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Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer’s disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.

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15

Gueniot, Florian, Sebastien Rubin, Pauline Bougaran, Alice Abelanet, Jean Luc Morel, Bruno Bontempi, Carole Proust, Pascale Dufourcq, Thierry Couffinhal, and Cecile Duplàa. "Targeting Pdzrn3 maintains adult blood-brain barrier and central nervous system homeostasis." Journal of Cerebral Blood Flow & Metabolism 42, no. 4 (October 13, 2021): 613–29. http://dx.doi.org/10.1177/0271678x211048981.

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Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer’s disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.

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16

Ciușdel, C. F., S. Coman, Cr Boldișor, T. Kessler, A. Muradyan, A. Kovachev, H. Lehrach, C. Wierling, and L. M. Itu. "Effect of Linearization in a WNT Signaling Model." Computational and Mathematical Methods in Medicine 2019 (June 10, 2019): 1–9. http://dx.doi.org/10.1155/2019/8461820.

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A nonlinear model consisting of a system of coupled ordinary differential equations (ODE), describing a biological process linked with cancer development, is linearized using Taylor series and tested against different magnitudes of input perturbations, in order to investigate the extent to which the linearization is accurate. The canonical wingless/integrated (WNT) signaling pathway is considered. The linearization procedure is described, and special considerations for linearization validity are analyzed. The analytical properties of nonlinear and linearized systems are studied, including aspects such as existence of steady state and initial value sensitivity. Linearization is a useful tool for speeding up drug response computations or for providing analytical answers to problems such as required drug concentrations. A Monte Carlo-based error testing workflow is employed to study the errors introduced by the linearization for different input conditions and parameter vectors. The deviations between the nonlinear and the linearized system were found to increase in a polynomial fashion w.r.t. the magnitude of tested perturbations. The linearized system closely followed the original one for perturbations of magnitude within 10% of the base input vector which yielded the state-space fixed point used for the linearization.

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17

Stewart, A. Keith, Yuan Xiao Zhu, Maryan Yahyapour, Armen Manoukian, and Sam E. Scanga. "Inhibition of Wnt Pathway Signaling by Thalidomide and Revlimid: Studies in a Drosophila Model System." Blood 104, no. 11 (November 16, 2004): 3356. http://dx.doi.org/10.1182/blood.v104.11.3356.3356.

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Abstract High throughput sequencing, gene expression profiling and protein biochemistry in myeloma have all consistently revealed elevated expression of wnt signaling pathways in malignant plasma cells. Indeed, downregulation of the Wnt pathway in myeloma cells has recently been shown to inhibit myeloma cellular proliferation. Preliminary pharmacogenomic studies have also suggested that hyperactivation of the wnt signaling antagonist DKK-1 is associated with response to the immunomodulators thalidomide and revlimid. The mechanism of action for these therapeutically active drugs is however by no means clear as multiple biologic consequences of treatment have been proposed. We report here use of a drosophila model to examine wnt signaling inhibition by these pharmaceuticals. We employed a unique drosophila larval imaginal disc culture system in which wnt pathway activity is monitored through control of LacZ expression by the distalless promoter. In this system 10uM of both thalidomide and revlimid reproducibly inhibit lacZ expression when compared with vehicle controls. Western blots of larva confirmed downregulation of expression of armadillo (the drosophila b-catenin homologue) by both drugs but particularly revlimid. Lithium Chloride is an inhibitor of the drosphila GSK3b homologue shaggy and thus mimics wnt signaling by stabilizing b-catenin. The effect of Lithium could not be overcome by thalidomide or revlimid indicating that the action of these drugs is upstream of shaggy (or GSK3). Next we employed a fly transgenic for wingless which is embryonic lethal. By adding either drug to larval culture medium the lethality of wingless expression was reversed. Indeed drosophila embryos fed thalidomide exhibited developmental plate abnormalities. We next sought evidence that similar effects were evident in revlimid treated human myeloma. As previously reported most myeloma cell lines studied expressed b-catenin and this protein was downregulated by revlimid treatment of human myeloma cell lines co-incident with inhibition of growth as measured by MTT assay. We sought, but failed to find evidence of up-regulation of the wnt signaling pathway antagonist DKK-1 using an ELISA assay on pre and post treatment serum samples in patients responding to thalidomide.The implications of wnt signaling inhibition as a primary or secondary readout of therapeutic efficiency in MM may be of substantial importance in subsequent design of drug therapies or combination therapies.

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18

Parr, B. A., M. J. Shea, G. Vassileva, and A. P. McMahon. "Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds." Development 119, no. 1 (September 1, 1993): 247–61. http://dx.doi.org/10.1242/dev.119.1.247.

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Mutation and expression studies have implicated the Wnt gene family in early developmental decision making in vertebrates and flies. In a detailed comparative analysis, we have used in situ hybridization of 8.0- to 9.5-day mouse embryos to characterize expression of all ten published Wnt genes in the central nervous system (CNS) and limb buds. Seven of the family members show restricted expression patterns in the brain. At least three genes (Wnt-3, Wnt-3a, and Wnt-7b) exhibit sharp boundaries of expression in the forebrain that may predict subdivisions of the region later in development. In the spinal cord, Wnt-1, Wnt-3, and Wnt-3a are expressed dorsally, Wnt-5a, Wnt-7a, and Wnt-7b more ventrally, and Wnt-4 both dorsally and in the floor plate. In the forelimb primordia, Wnt-3, Wnt-4, Wnt-6 and Wnt-7b are expressed fairly uniformly throughout the limb ectoderm. Wnt-5a RNA is distributed in a proximal to distal gradient through the limb mesenchyme and ectoderm. Along the limb's dorsal-ventral axis, Wnt-5a is expressed in the ventral ectoderm and Wnt-7a in the dorsal ectoderm. We discuss the significance of these patterns of restricted and partially overlapping domains of expression with respect to the putative function of Wnt signalling in early CNS and limb development.

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19

Mudri, Dunja, Ines Bilić Ćurčić, Lucija Meštrović, Ivica Mihaljević, and Tomislav Kizivat. "Hyperthyroidism and Wnt Signaling Pathway: Influence on Bone Remodeling." Metabolites 13, no. 2 (February 6, 2023): 241. http://dx.doi.org/10.3390/metabo13020241.

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Graves’ disease is an autoimmune disease of the thyroid gland, characterized by increased production of thyroid hormones, which can affect many different organ systems in the body. Among other problems, it can cause disorders of the skeletal system, shortening the bone remodeling cycle and causing a decrease in bone density. The Wnt cascade signaling pathway and the β-catenin, as a part of the canonical Wnt pathway, also play roles in maintaining bone mass. Inhibition of the Wnt pathway can cause bone loss, and its stimulation can increase it. The Wnt signaling pathway influences the effectiveness of thyroid hormones by affecting receptors for thyroid hormones and deiodinase, while thyroid hormones can change levels of β-catenin within the cell cytoplasm. This indicates that the Wnt pathway and thyroid hormone levels, including hyperthyroidism, are linked and may act together to change bone density. In this review article, we attempt to explain the interplay between thyroid hormones and the Wnt pathway on bone density, with a focus on directions for further research and treatment options.

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20

Grigorie, D. "The Crucial Role of the WNT System in Bone Remodelling." Acta Endocrinologica (Bucharest) 14, no. 1 (2018): 90–101. http://dx.doi.org/10.4183/aeb.2018.90.

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21

Petrova, Iveta M., Martijn J. Malessy, Joost Verhaagen, Lee G. Fradkin, and Jasprina N. Noordermeer. "Wnt Signaling through the Ror Receptor in the Nervous System." Molecular Neurobiology 49, no. 1 (August 30, 2013): 303–15. http://dx.doi.org/10.1007/s12035-013-8520-9.

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22

Inestrosa, N. C., and L. Varela-Nallar. "Wnt signaling in the nervous system and in Alzheimer's disease." Journal of Molecular Cell Biology 6, no. 1 (February 1, 2014): 64–74. http://dx.doi.org/10.1093/jmcb/mjt051.

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23

Green, David, Amy E. Whitener, Saurav Mohanty, and Arne C. Lekven. "Vertebrate nervous system posteriorization: Grading the function of Wnt signaling." Developmental Dynamics 244, no. 3 (December 16, 2014): 507–12. http://dx.doi.org/10.1002/dvdy.24230.

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24

Aghaizu, Nozie D., Hanqing Jin, and Paul J. Whiting. "Dysregulated Wnt Signalling in the Alzheimer’s Brain." Brain Sciences 10, no. 12 (November 24, 2020): 902. http://dx.doi.org/10.3390/brainsci10120902.

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The Wnt signalling system is essential for both the developing and adult central nervous system. It regulates numerous cellular functions ranging from neurogenesis to blood brain barrier biology. Dysregulated Wnt signalling can thus have significant consequences for normal brain function, which is becoming increasingly clear in Alzheimer’s disease (AD), an age-related neurodegenerative disorder that is the most prevalent form of dementia. AD exhibits a range of pathophysiological manifestations including aberrant amyloid precursor protein processing, tau pathology, synapse loss, neuroinflammation and blood brain barrier breakdown, which have been associated to a greater or lesser degree with abnormal Wnt signalling. Here we provide a comprehensive overview of the role of Wnt signalling in the CNS, and the research that implicates dysregulated Wnt signalling in the ageing brain and in AD pathogenesis. We also discuss the opportunities for therapeutic intervention in AD via modulation of the Wnt signalling pathway, and highlight some of the challenges and the gaps in our current understanding that need to be met to enable that goal.

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25

Wesslowski, Janine, Pawel Kozielewicz, Xianxian Wang, Haijun Cui, Hannes Schihada, Dominique Kranz, Pradhipa Karuna M, et al. "eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length Frizzled." Journal of Biological Chemistry 295, no. 26 (May 7, 2020): 8759–74. http://dx.doi.org/10.1074/jbc.ra120.012892.

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The Wingless/Int1 (Wnt) signaling system plays multiple, essential roles in embryonic development, tissue homeostasis, and human diseases. Although many of the underlying signaling mechanisms are becoming clearer, the binding mode, kinetics, and selectivity of 19 mammalian WNTs to their receptors of the class Frizzled (FZD1–10) remain obscure. Attempts to investigate Wnt-FZD interactions are hampered by the difficulties in working with Wnt proteins and their recalcitrance to epitope tagging. Here, we used a fluorescently tagged version of mouse Wnt-3a for studying Wnt-FZD interactions. We observed that the enhanced GFP (eGFP)-tagged Wnt-3a maintains properties akin to wild-type (WT) Wnt-3a in several biologically relevant contexts. The eGFP-tagged Wnt-3a was secreted in an evenness interrupted (EVI)/Wntless-dependent manner, activated Wnt/β-catenin signaling in 2D and 3D cell culture experiments, promoted axis duplication in Xenopus embryos, stimulated low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation in cells, and associated with exosomes. Further, we used conditioned medium containing eGFP-Wnt-3a to visualize its binding to FZD and to quantify Wnt-FZD interactions in real time in live cells, utilizing a recently established NanoBRET-based ligand binding assay. In summary, the development of a biologically active, fluorescent Wnt-3a reported here opens up the technical possibilities to unravel the intricate biology of Wnt signaling and Wnt-receptor selectivity.

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26

Kitajewski, J., J. O. Mason, and H. E. Varmus. "Interaction of Wnt-1 proteins with the binding protein BiP." Molecular and Cellular Biology 12, no. 2 (February 1992): 784–90. http://dx.doi.org/10.1128/mcb.12.2.784-790.1992.

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The mouse Wnt-1 gene, a target for insertional activation in mouse mammary tumor virus-induced mammary tumors, encodes poorly secreted, cysteine-rich glycoproteins required for proper central nervous system development. We have been analyzing the biosynthesis of Wnt-1 proteins in several cell lines that express Wnt-1 cDNA from heterologous promoters. A protein of 78 kDa was found to be associated with the intracellular forms of Wnt-1 proteins in mammalian and avian cells by using multiple antisera against Wnt-1 proteins. We have identified p78 as the binding protein BiP with anti-BiP antisera and by its release from Wnt-1 immunoprecipitates upon incubation with MgCl2 and ATP. Experiments with a Wnt-1 mutant that lacks the sequence encoding the signal peptide indicates that Wnt-1 proteins must enter the secretory pathway in order to interact with BiP. We demonstrate that Wnt-1 proteins are associated with BiP in cells in which active Wnt-1 proteins are produced, such as a cultured mammary epithelial cell line and Wnt-1 transgenic mouse mammary tumor cells. The association of Wnt-1 proteins with BiP may be a factor in determining the efficiency of secretion of Wnt-1 gene products.

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27

Kitajewski, J., J. O. Mason, and H. E. Varmus. "Interaction of Wnt-1 proteins with the binding protein BiP." Molecular and Cellular Biology 12, no. 2 (February 1992): 784–90. http://dx.doi.org/10.1128/mcb.12.2.784.

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The mouse Wnt-1 gene, a target for insertional activation in mouse mammary tumor virus-induced mammary tumors, encodes poorly secreted, cysteine-rich glycoproteins required for proper central nervous system development. We have been analyzing the biosynthesis of Wnt-1 proteins in several cell lines that express Wnt-1 cDNA from heterologous promoters. A protein of 78 kDa was found to be associated with the intracellular forms of Wnt-1 proteins in mammalian and avian cells by using multiple antisera against Wnt-1 proteins. We have identified p78 as the binding protein BiP with anti-BiP antisera and by its release from Wnt-1 immunoprecipitates upon incubation with MgCl2 and ATP. Experiments with a Wnt-1 mutant that lacks the sequence encoding the signal peptide indicates that Wnt-1 proteins must enter the secretory pathway in order to interact with BiP. We demonstrate that Wnt-1 proteins are associated with BiP in cells in which active Wnt-1 proteins are produced, such as a cultured mammary epithelial cell line and Wnt-1 transgenic mouse mammary tumor cells. The association of Wnt-1 proteins with BiP may be a factor in determining the efficiency of secretion of Wnt-1 gene products.

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28

Van Den Berg, David J., Arun K. Sharma, Edward Bruno, and Ron Hoffman. "Role of Members of the Wnt Gene Family in Human Hematopoiesis." Blood 92, no. 9 (November 1, 1998): 3189–202. http://dx.doi.org/10.1182/blood.v92.9.3189.

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Abstract The hematopoietic system is derived from ventral mesoderm. A number of genes that are important in mesoderm development have been identified including members of the transforming growth factor-β (TGF-β) superfamily, the fibroblast growth factor (FGF) family, and the Wnt gene family. Because TGF-β plays a pleiotropic role in hematopoiesis, we wished to determine if other genes that are important in mesoderm development, specifically members of theWnt gene family, may play a role in hematopoiesis. Three members of the Wnt gene family (Wnt-5A, Wnt-2B, and Wnt-10B) were identified and cloned from human fetal bone stromal cells. These genes are expressed to varying levels in hematopoietic cell lines derived from T cells, B cells, myeloid cells, and erythroid cells; however, only Wnt-5A was expressed in CD34+Lin− primitive progenitor cells. The in vitro biological activity of these Wnt genes on CD34+Lin− hematopoietic progenitors was determined in a feeder cell coculture system and assayed by quantitating progenitor cell numbers, CD34+ cell numbers, and numbers of differentiated cell types. The number of hematopoietic progenitor cells was markedly affected by exposure to stromal cell layers expressing Wnt genes with 10- to 20-fold higher numbers of mixed colony-forming units (CFU-MIX), 1.5- to 2.6-fold higher numbers of CFU-granulocyte macrophage (CFU-GM), and greater than 10-fold higher numbers of burst-forming units-erythroid (BFU-E) in the Wnt-expressing cocultures compared with the controls. Colony formation by cells expanded on theWnt-expressing cocultures was similar for each of the three genes, indicating similar action on primitive progenitor cells; however, Wnt-10B showed differential activity on erythroid progenitors (BFU-E) compared with Wnt-5A and Wnt-2B. Cocultures containing Wnt-10B alone or in combination with all three Wnt genes had threefold to fourfold lower BFU-E colony numbers than the Wnt-5A– or Wnt-2B–expressing cocultures. The frequency of CD34+ cells was higher inWnt-expressing cocultures and cellular morphology indicated that coculture in the presence of Wnt genes resulted in higher numbers of less differentiated hematopoietic cells and fewer mature cells than controls. These data indicate that the gene products of theWnt family function as hematopoietic growth factors, and that they may exhibit higher specificity for earlier progenitor cells. © 1998 by The American Society of Hematology.

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29

Van Den Berg, David J., Arun K. Sharma, Edward Bruno, and Ron Hoffman. "Role of Members of the Wnt Gene Family in Human Hematopoiesis." Blood 92, no. 9 (November 1, 1998): 3189–202. http://dx.doi.org/10.1182/blood.v92.9.3189.421k45_3189_3202.

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Анотація:

The hematopoietic system is derived from ventral mesoderm. A number of genes that are important in mesoderm development have been identified including members of the transforming growth factor-β (TGF-β) superfamily, the fibroblast growth factor (FGF) family, and the Wnt gene family. Because TGF-β plays a pleiotropic role in hematopoiesis, we wished to determine if other genes that are important in mesoderm development, specifically members of theWnt gene family, may play a role in hematopoiesis. Three members of the Wnt gene family (Wnt-5A, Wnt-2B, and Wnt-10B) were identified and cloned from human fetal bone stromal cells. These genes are expressed to varying levels in hematopoietic cell lines derived from T cells, B cells, myeloid cells, and erythroid cells; however, only Wnt-5A was expressed in CD34+Lin− primitive progenitor cells. The in vitro biological activity of these Wnt genes on CD34+Lin− hematopoietic progenitors was determined in a feeder cell coculture system and assayed by quantitating progenitor cell numbers, CD34+ cell numbers, and numbers of differentiated cell types. The number of hematopoietic progenitor cells was markedly affected by exposure to stromal cell layers expressing Wnt genes with 10- to 20-fold higher numbers of mixed colony-forming units (CFU-MIX), 1.5- to 2.6-fold higher numbers of CFU-granulocyte macrophage (CFU-GM), and greater than 10-fold higher numbers of burst-forming units-erythroid (BFU-E) in the Wnt-expressing cocultures compared with the controls. Colony formation by cells expanded on theWnt-expressing cocultures was similar for each of the three genes, indicating similar action on primitive progenitor cells; however, Wnt-10B showed differential activity on erythroid progenitors (BFU-E) compared with Wnt-5A and Wnt-2B. Cocultures containing Wnt-10B alone or in combination with all three Wnt genes had threefold to fourfold lower BFU-E colony numbers than the Wnt-5A– or Wnt-2B–expressing cocultures. The frequency of CD34+ cells was higher inWnt-expressing cocultures and cellular morphology indicated that coculture in the presence of Wnt genes resulted in higher numbers of less differentiated hematopoietic cells and fewer mature cells than controls. These data indicate that the gene products of theWnt family function as hematopoietic growth factors, and that they may exhibit higher specificity for earlier progenitor cells. © 1998 by The American Society of Hematology.

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Riddiough, Georgina E., Theodora Fifis, Katrina A. Walsh, Vijayaragavan Muralidharan, Christopher Christophi, Bang M. Tran, Elizabeth Vincan, and Marcos V. Perini. "Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis." Cancers 13, no. 11 (May 31, 2021): 2734. http://dx.doi.org/10.3390/cancers13112734.

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(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.

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Nothelfer, Katharina, Florian Obermayr, Nadine Belz, Ellen Reinartz, Petra M. Bareiss, Hans-Jörg Bühring, Rudi Beschorner, and Lothar Just. "Expression of the Wnt Receptor Frizzled-4 in the Human Enteric Nervous System of Infants." Stem Cells International 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/9076823.

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The Wnt signalling pathway plays a crucial role in the development of the nervous system. This signalling cascade is initiated upon binding of the secreted Wnt ligand to a member of the family of frizzled receptors. In the present study, we analysed the presence of frizzled-4 in the enteric nervous system of human infants. Frizzled-4 could be identified by immunohistochemistry in a subpopulation of enteric neuronal and glial cells in the small and large intestine. Detection of frizzled-4 in the tunica muscularis by RT-PCR confirmed this receptor’s expression on the mRNA level. Interestingly, we observed distinct cell populations that co-expressed frizzled-4 with the intermediate filament protein nestin and the neurotrophin receptorp75NTR, which have been reported to be expressed in neural progenitor cells. Flow cytometry analysis revealed that 60% ofp75NTRpositive cells of the tunica muscularis were positive for frizzled-4. Additionally, in pathological samples of Hirschsprung’s disease, the expression of this Wnt receptor correlated with the number of myenteric ganglion cells and decreased from normoganglionic to aganglionic areas of large intestine. The expression pattern of frizzled-4 indicates that this Wnt receptor could be involved in postnatal development and/or function of the enteric nervous system.

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Thorne, Curtis A., Bonnie Lafleur, Michelle Lewis, Alison J. Hanson, Kristin K. Jernigan, David C. Weaver, Kari A. Huppert, et al. "A Biochemical Screen for Identification of Small-Molecule Regulators of the Wnt Pathway Using Xenopus Egg Extracts." Journal of Biomolecular Screening 16, no. 9 (August 21, 2011): 995–1006. http://dx.doi.org/10.1177/1087057111416657.

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Misregulation of the Wnt pathway has been shown to be responsible for a variety of human diseases, most notably cancers. Screens for inhibitors of this pathway have been performed almost exclusively using cultured mammalian cells or with purified proteins. We have previously developed a biochemical assay using Xenopus egg extracts to recapitulate key cytoplasmic events in the Wnt pathway. Using this biochemical system, we show that a recombinant form of the Wnt coreceptor, LRP6, regulates the stability of two key components of the Wnt pathway (β-catenin and Axin) in opposing fashion. We have now fused β-catenin and Axin to firefly and Renilla luciferase, respectively, and demonstrate that the fusion proteins behave similarly as their wild-type counterparts. Using this dual luciferase readout, we adapted the Xenopus extracts system for high-throughput screening. Results from these screens demonstrate signal distribution curves that reflect the complexity of the library screened. Of several compounds identified as cytoplasmic modulators of the Wnt pathway, one was further validated as a bona fide inhibitor of the Wnt pathway in cultured mammalian cells and Xenopus embryos. We show that other embryonic pathways may be amendable to screening for inhibitors/modulators in Xenopus egg extracts.

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Soomro, Shahid Hussain, Jifu Jie, and Hui Fu. "Oligodendrocytes Development and Wnt Signaling Pathway." International Journal of Human Anatomy 1, no. 3 (October 29, 2018): 17–35. http://dx.doi.org/10.14302/issn.2577-2279.ijha-18-2407.

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Oligodendrocytes are specialized glial cell in central nervous system (CNS) responsible for the formation of myelin sheath around the axon. Oligodendrocyte proliferation and differentiation is regulated by Wnt signaling pathway, at various stages. However, different study groups have described controversial conclusions about the effect of Wnt on oligodendrocytes precursor cells (OPCs) development. Initially it has been proposed that Wnt pathway negatively regulates the OPCs proliferation and differentiation but recently some studies have described that Wnt promotes the differentiation of OPCs. After carefully reviewing the literature, we believe that Wnt play multiple roles in OPCs differentiation and its function is time (stage) and dose sensitive. Low to moderate activation of Wnt promotes OPC development, while too much or too low is inhibitory. Current evidences also suggested that in early developmental stages, Wnt inhibits the OPCs formation from neural progenitors and differentiation into immature oligodendrocytes. But in late stages Wnt plays promoting role in differentiation and maturation of oligodendrocytes. This review summarized the updated information regarding the critical role of Wnt signaling cascade in proliferation and differentiation of OPCs.

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34

Satterfield, M. Carey, Gwonhwa Song, Kanako Hayashi, Fuller W. Bazer, and Thomas E. Spencer. "Progesterone regulation of the endometrial WNT system in the ovine uterus." Reproduction, Fertility and Development 20, no. 8 (2008): 935. http://dx.doi.org/10.1071/rd08069.

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WNT signalling regulates cell proliferation, differentiation, polarity and organisation. The present study investigated the effects of progesterone (P4) on the endometrial WNT system in relation to blastocyst development and growth in sheep. Ewes received daily intramuscular injections of either corn oil (CO) vehicle or 25 mg P4 from 36 h after mating (Day 0) until hysterectomy on Day 9 or 12. Another group received P4 until Day 8 and 75 mg mifepristone (RU486) from Day 8 to Day 12. Early P4 treatment increased blastocyst growth on Days 9 and 12, whereas no blastocysts were recovered from P4 + RU486-treated ewes. Levels of WNT2 mRNA in the stroma and WNT11 and WNT7A mRNAs in the endometrial luminal epithelia (LE) were reduced in P4 + RU486-treated ewes on Day 9, whereas WNT11 mRNA was reduced in the endometria of both P4- and P4 + RU486-treated ewes on Day 12. On Day 12, WNT2 mRNA was increased in the stroma, WNT7A mRNA was increased in the LE and WNT5A mRNA was increased in the LE and stroma of P4 + RU486- compared with P4-treated ewes. DKK1 mRNA was absent in the endometrial stroma of P4 + RU486-treated ewes. Expression of transcription factor 7 like-2 (TCF7L2) was transiently increased in endometrial epithelia of P4-treated ewes on Day 9, but decreased in these ewes on Day 12. MSX1 mRNA was decreased by P4 treatment on Day 9 and levels of both MSX1 and MSX2 mRNA were higher in P4 + RU486-treated ewes on Day 12. Thus, P4 modulates the endometrial WNT system and elicits a transient decline in selected WNT pathways and signalling components, which is hypothesised to alter tight and adherens junctions, thereby stimulating blastocyst growth and development.

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Kulakova, Anastasiia S. "Role of proteins STAT/SOCS and WNT signaling system in obesity." Journal of Ural Medical Academic Science 19, no. 3 (2022): 254–62. http://dx.doi.org/10.22138/2500-0918-2022-19-3-254-262.

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Violation of adipogenesis leads to the formation of hypertrophic obesity. Hypertrophied adipocytes produce a large number of cytokines, including TNF-α, IL-6, IL-1β, IL-10. The mechanism of adipogenesis is complex and diverse, as it is influenced by numerous factors, including components of the STAT and WNT signaling systems. The search for possible markers of the development of metabolic diseases has led to interest in studying the involvement of STAT and WNT proteins, signaling systems, in the implementation of cytokine effects in obesity. The aim of the study was to assess the serum levels of cytokines TNF-α, IL-6, IL-1β, IL-10 in patients with overweight, obesity and metabolic syndrome, as well as the relationship of these indicators with the concentration of STAT and WNT proteins signaling systems. Materials and methods. The study included 118 people, including 28 people with overweight, 28 obese patients without signs of metabolic syndrome, 32 patients with metabolic syndrome, 30 apparently healthy individuals with normal body weight, matched by sex and age. The concentration of proteins in the blood serum was determined by enzyme immunoassay. Quantitative indicators were evaluated for compliance with the normal distribution using the Kolmogorov-Smirnov test. In the absence of a normal distribution, quantitative data were described using the median (Me) and the lower and upper quartiles (Q1 – Q3). The direction and closeness of the correlation between two quantitative indicators were assessed using the Spearman rank correlation coefficient (with a non-normal distribution of indicators). Differences between the indicators were considered statistically significant at p<0.05. Results. In patients with metabolic syndrome, obesity and overweight, a statistically significant increase in the concentration of pro- and anti-inflammatory (TNF-α, IL-6, IL-1β, IL-10) cytokines was found relative to the comparison group; either a direct noticeable or a direct moderate correlation was established between the level of pro-inflammatory cytokines and the level of STAT and WNT proteins signaling systems. The obtained data on the increase in the levels of the corresponding cytokines (TNF-α, IL-6, IL-1β, IL-10) in patients with overweight, obesity and metabolic syndrome against the background of changes in the concentration of proteins of the WNT signaling pathway and the level of STAT/SOCS proteins 1, 3, 6 can serve as biomarkers for early detection of metabolic disorders.

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You, Zongbing, Daniel Saims, Shaoqiong Chen, Zhaocheng Zhang, Denis C. Guttridge, Kun-liang Guan, Ormond A. MacDougald, et al. "Wnt signaling promotes oncogenic transformation by inhibiting c-Myc–induced apoptosis." Journal of Cell Biology 157, no. 3 (April 29, 2002): 429–40. http://dx.doi.org/10.1083/jcb.200201110.

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Aberrant activation of the Wnt/β-catenin signaling pathway is associated with numerous human cancers and often correlates with the overexpression or amplification of the c-myc oncogene. Paradoxical to the cellular transformation potential of c-Myc is its ability to also induce apoptosis. Using an inducible c-MycER expression system, we found that Wnt/β-catenin signaling suppressed apoptosis by inhibiting c-Myc–induced release of cytochrome c and caspase activation. Both cyclooxygenase 2 and WISP-1 were identified as effectors of the Wnt-mediated antiapoptotic signal. Soft agar assays showed that neither c-Myc nor Wnt-1 alone was sufficient to induce cellular transformation, but that Wnt and c-Myc coordinated in inducing transformation. Furthermore, coexpression of Wnt-1 and c-Myc induced high-frequency and rapid tumor growth in nude mice. Extensive apoptotic bodies were characteristic of c-Myc–induced tumors, but not tumors induced by coactivation of c-Myc and Wnt-1, indicating that the antiapoptotic function of Wnt-1 plays a critical role in the synergetic action between c-Myc and Wnt-1. These results elucidate the molecular mechanisms by which Wnt/β-catenin inhibits apoptosis and provide new insight into Wnt signaling-mediated oncogenesis.

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Shu, Yang, Min Xiang, Pei Zhang, Guangjian Qi, Feng He, Qian Zhang, Zheng Zhang, et al. "Wnt-5a Promotes Neural Development and Differentiation by Regulating CDK5 via Ca2+/Calpain Pathway." Cellular Physiology and Biochemistry 51, no. 6 (2018): 2604–15. http://dx.doi.org/10.1159/000495932.

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Background/Aims: The Wnt signaling pathway has essential functions in the central nervous system, where it regulates the major physiological functions of neurons, including development, differentiation, and plasticity. Wnt signaling controls these cellular events; however, how Wnt pathways integrate into a coherent developmental program remains unclear. Methods: The expression and secretion of different WNT ligands (Wnt-1, Wnt-3a, Wnt-4, Wnt-5a, Wnt-11), and the levels and activities of cyclin-dependent kinases (CDK2, CDK4, CDK6/cyclin D, cyclin E) or CDK5 (CDK5/p35 and p25) were measured in Rat cortex at different embryonic stages, and in RA/BDNF-induced differentiated SH-SY5Y cell model, by Quantitative real-time PCR (qPCR), western blotting, ELISA, and in vitro CDK5 kinase assays. MAP2-BrdU double staining was used to assess cell differentiation and cell cycle exit in an RA/BDNF-induced differentiated SH-SY5Y cell model. The effects of CDK5 and Ca2+/calpain signaling were assessed using specific chemical inhibitors. Results: We found that Wnt-1 was unchanged and Wnt-3a was attenuated, whereas Wnt-4, Wnt-5a, and Wnt-11 were markedly up-regulated, during the development of neurons and differentiated SH-SY5Y cells. Simultaneously, the activity of CDK5 was elevated. Furthermore, we describe crosstalk between non-canonical Wnt signaling and CDK5 in the development of neurons and differentiated SH-SY5Y cells. Wnt-5a, a non-canonical Wnt ligand, regulated CDK5 via Ca2+/calpain signaling in both neuronal development and differentiation. Inhibition of Wnt-5a diminished CDK5 kinase activity via the Ca2+/calpain pathway, thereby attenuating RA-BDNF induced SH-SY5Y cell differentiation. Conclusion: Wnt-5a signaling is a significant regulator of neuronal development and differentiation and upregulates CDK5 kinase activity via Ca2+/calpain signaling.

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Gruszka, Alicja M., Debora Valli, and Myriam Alcalay. "Wnt Signalling in Acute Myeloid Leukaemia." Cells 8, no. 11 (November 7, 2019): 1403. http://dx.doi.org/10.3390/cells8111403.

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Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.

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Desai, Jigar S., Lovely Mae F. Lawas, Ashlee M. Valente, Adam R. Leman, Dmitry O. Grinevich, S. V. Krishna Jagadish, and Colleen J. Doherty. "Warm nights disrupt transcriptome rhythms in field-grown rice panicles." Proceedings of the National Academy of Sciences 118, no. 25 (June 21, 2021): e2025899118. http://dx.doi.org/10.1073/pnas.2025899118.

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In rice, a small increase in nighttime temperature reduces grain yield and quality. How warm nighttime temperatures (WNT) produce these detrimental effects is not well understood, especially in field conditions where the typical day-to-night temperature fluctuation exceeds the mild increase in nighttime temperature. We observed genome-wide disruption of gene expression timing during the reproductive phase in field-grown rice panicles acclimated to 2 to 3 °C WNT. Transcripts previously identified as rhythmically expressed with a 24-h period and circadian-regulated transcripts were more sensitive to WNT than were nonrhythmic transcripts. The system-wide perturbations in transcript levels suggest that WNT disrupt the tight temporal coordination between internal molecular events and the environment, resulting in reduced productivity. We identified transcriptional regulators whose predicted targets are enriched for sensitivity to WNT. The affected transcripts and candidate regulators identified through our network analysis explain molecular mechanisms driving sensitivity to WNT and identify candidates that can be targeted to enhance tolerance to WNT.

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Chung, Dong Jin, та Min Young Chung. "Bone Forming Effect of PTH through Wnt/β-catenin Signaling System". Journal of Korean Endocrine Society 22, № 6 (2007): 407. http://dx.doi.org/10.3803/jkes.2007.22.6.407.

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Tong, Shan, Qingwei Ji, Yu Du, Xiaogang Zhu, Caizhong Zhu, and Yujie Zhou. "Sfrp5/Wnt Pathway: A Protective Regulatory System in Atherosclerotic Cardiovascular Disease." Journal of Interferon & Cytokine Research 39, no. 8 (August 2019): 472–82. http://dx.doi.org/10.1089/jir.2018.0154.

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Becker, Jürgen, and Jörg Wilting. "WNT signaling, the development of the sympathoadrenal–paraganglionic system and neuroblastoma." Cellular and Molecular Life Sciences 75, no. 6 (October 22, 2017): 1057–70. http://dx.doi.org/10.1007/s00018-017-2685-8.

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Li, Xing-Yao, Yuan-Yuan Wang, Chun-Mao Yuan, Xiao-Jiang Hao, and Yan Li. "A reporter gene system for screening inhibitors of Wnt signaling pathway." Natural Products and Bioprospecting 3, no. 1 (January 9, 2013): 24–28. http://dx.doi.org/10.1007/s13659-012-0094-0.

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Giuliani, Nicola, Francesca Morandi, Rita Rizzato, Sara Tagliaferri, and Vittorio Rizzoli. "Effects of Human Myeloma Cells on WNT Signaling System in Human Bone Marrow Osteoprogenitor Cells." Blood 106, no. 11 (November 16, 2005): 2503. http://dx.doi.org/10.1182/blood.v106.11.2503.2503.

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Abstract The mechanisms by which multiple myeloma (MM) cells inhibit osteoblast formation are not completely clear. Recently we have demonstrated that human myeloma cells block the critical osteogenic transcription factor RUNX2 in osteoprogenitor cells inhibiting the osteoblastogenesis. However several data indicate that WNT signaling is also important, at least in murine system, in the regulation of osteoblast formation. Given that MM cells produce the WNT inhibitor DKK-1 that correlated with the presence of bone lesions, we have investigated the potential effects of human myeloma cells on WNT signaling in human bone marrow (BM) osteoprogenitor cells. First we checked human myeloma cell lines (HMCLs) (XG-1, XG-6, RPMI-8226, U266, OPM-2, JJN3) and purified CD138+ MM cells for the expression of the WNT inhibitors DKK-1 and secreted Frizzled-related proteins (sFRP)-1,-2,-3,-4 finding that 50% of HMCLs and 70% of MM patients were positive for DKK-1. A similar pattern of expression was observed for the sFRP-3 whereas MM cells were negative either for sFRP-2 with the exception of U266 or for sFRP-1 and sFRP-4. Further, we performed a co-culture system with BM osteoprogenitor cells (PreOB), obtained after two weeks of differentiation and MM cells, in the presence or absence of a transwell system for 12–72 hours. After the co-culture period in the cell-to-cell contact condition MM cells were depleted to avoid their contamination. WNT signaling pathway was analyzed in PreOB by microarray using a specific Oligo GEArray® kit and further evaluated by RT-PCR and western blot analysis on selected molecules. Any effect on the expression of DKK-1,-2,-3,-4 as well as sFRP1,-2,-3,-4 by PreOB was not observed. these results was also confirmed for DKK-1 and sFRPs by western blot. An inhibitory effect on beta-catenin and on DKK-1 receptor LRP5 as well as an up-regulation of the osteoblast regulators WISP-1 and WISP-2 and of WNT5a have been observed. The study of beta-catenin signaling was deepened in both HMCLs and PreOB using either specific antibodies for the active de-phosphorylated form and inactive phosphorilated one or ELISA assay to evaluate the total levels of beta-catenin in both cytosolic and nuclear extracts. We failed to observe an inhibitory effect on nuclear levels of active beta-catenin and total beta-catenin in PreOB after co-culture in both cell-to-cell contact and transwell conditions by westernblot and immunofluorescence. In addition any significant effect on the transcription factors LEF-1 and TCF was not observed in PreOB cells after the co-culture using the array and western blot. On the other hand we found that active beta-catenin levels were completely down-regulated in both cytosolic and nuclear extracts in the majority of HMCLs and MM cells tested suggesting that canonical WNT signaling was completely inhibited in myeloma cells but not in PreOB. The involvement of WNT signaling in the inhibition of osteoblastogenesis by was further evaluated testing the effect Wnt3a and DKK-1 on beta-catenin levels and osteoblast formation in vitro. Wnt3 stimulation did not restore the inhibitory effect induced by MM cells in co-culture on bone nodule formation whereas DKK-1 showed an inhibitory effect on beta-catenin and bone nodule formation only at very high concentrations. Our data indicate that MM cells may affect WNT signaling in human osteoprogenitor cells even if we failed to observe a block of this pathways suggesting that other mechanisms could be involved in DKK-1 mediated bone destruction in MM.

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González-Sancho, José Manuel, María Jesús Larriba, and Alberto Muñoz. "Wnt and Vitamin D at the Crossroads in Solid Cancer." Cancers 12, no. 11 (November 19, 2020): 3434. http://dx.doi.org/10.3390/cancers12113434.

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Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)2D3. Here we review the mechanisms by which 1,25(OH)2D3 inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.

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46

Grandy, David, Jufang Shan, Xinxin Zhang, Sujata Rao, Shailaja Akunuru, Hongyan Li, Yanhui Zhang, et al. "Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled." Journal of Biological Chemistry 284, no. 24 (April 21, 2009): 16256–63. http://dx.doi.org/10.1074/jbc.m109.009647.

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Dishevelled (Dvl) is an essential protein in the Wnt signaling pathways; it uses its PDZ domain to transduce the Wnt signals from the membrane receptor Frizzled to downstream components. Here, we report identifying a drug-like small molecule compound through structure-based ligand screening and NMR spectroscopy and show the compound to interact at low micromolar affinity with the PDZ domain of Dvl. In a Xenopus testing system, the compound could permeate the cell membrane and block the Wnt signaling pathways. In addition, the compound inhibited Wnt signaling and reduced the levels of apoptosis in the hyaloid vessels of eye. Moreover, this compound also suppressed the growth of prostate cancer PC-3 cells. These biological effects suggest that by blocking the PDZ domain of Dvl, the compound identified in our studies effectively inhibits the Wnt signaling and thus provides a useful tool for studies dissecting the Wnt signaling pathways.

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47

Wan, Wenbin, Shijin Xia, Bill Kalionis, Lumei Liu, and Yaming Li. "The Role of Wnt Signaling in the Development of Alzheimer’s Disease: A Potential Therapeutic Target?" BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/301575.

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Accumulating evidence supports a key role for Wnt signaling in the development of the central nervous system (CNS) during embryonic development and in the regulation of the structure and function of the adult brain. Alzheimer’s disease (AD) is the most common form of senile dementia, which is characterized byβ-amyloid (Aβ) deposition in specific brain regions. However, the molecular mechanism underlying AD pathology remains elusive. Dysfunctional Wnt signaling is associated with several diseases such as epilepsy, cancer, metabolic disease, and AD. Increasing evidence suggests that downregulation of Wnt signaling, induced by Aβ, is associated with disease progression of AD. More importantly, persistent activation of Wnt signaling through Wnt ligands, or inhibition of negative regulators of Wnt signaling, such as Dickkopf-1 (DKK-1) and glycogen synthase kinase-3β(GSK-3β) that are hyperactive in the disease state, is able to protect against Aβtoxicity and ameliorate cognitive performance in AD. Together, these data suggest that Wnt signaling might be a potential therapeutic target of AD. Here, we review recent studies related to the progression of AD where Wnt signaling might be relevant and participate in the development of the disease. Then, we focus on the potential relevance of manipulating the Wnt signaling pathway for the treatment of AD.

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Jiang, Xin, Yingjun Guan, Zhenhan Zhao, Fandi Meng, Xuemei Wang, Xueshuai Gao, Jinmeng Liu, et al. "Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis." Cells 10, no. 4 (April 8, 2021): 839. http://dx.doi.org/10.3390/cells10040839.

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The WNT signaling pathway plays an important role in the physiological and pathophysiological processes of the central nervous system and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We reviewed the literature pertinent to WNT/β–catenin signaling in ALS from cellular studies, animal models, and human clinical trials. WNT, WNT receptors, and other components of the WNT signaling pathway are expressed in both ALS patients and transgenic mice, and are involved in the pathogenesis of ALS. Studies have shown that abnormal activation of the WNT/β–catenin signaling pathway is related to neuronal degeneration and glial cell proliferation. WNT/Ca2+ signaling is associated with the pro–inflammatory phenotype of microglia; data on the muscle skeletal receptor Tyr kinase receptor in superoxide dismutase–1–G93A mice indicate that gene therapy is necessary for successful treatment of ALS. The varying profiles of lipoprotein receptor–related protein 4 antibodies in different ethnic groups suggest that individual treatment and multifactorial personalized approaches may be necessary for effective ALS therapy. In conclusion, the WNT signaling pathway is important to the ALS disease process, making it a likely therapeutic target.

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Young, C. S., Marina Kitamura, Stephen Hardy та Jan Kitajewski. "Wnt-1 Induces Growth, Cytosolic β-Catenin, and Tcf/Lef Transcriptional Activation in Rat-1 Fibroblasts". Molecular and Cellular Biology 18, № 5 (1 травня 1998): 2474–85. http://dx.doi.org/10.1128/mcb.18.5.2474.

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ABSTRACT Genetic evidence suggests that regulation of β-catenin and regulation of Tcf/Lef family transcription factors are downstream events of the Wnt signal transduction pathway. However, a direct link between Wnt activity and Tcf/Lef transcriptional activation has yet to be established. In this study, we show that Wnt-1 induces a growth response in a cultured mammalian cell line, Rat-1 fibroblasts. Wnt-1 induces serum-independent cellular proliferation of Rat-1 fibroblasts and changes in morphology. Rat-1 cells stably expressing Wnt-1 (Rat-1/Wnt-1) show a constitutive up-regulation of cytosolic β-catenin, while membrane-associated β-catenin remains unaffected. Induction of cytosolic β-catenin in Rat-1/Wnt-1 cells is correlated with activation of a Tcf-responsive transcriptional element. We thus provide evidence that Wnt-1 induces Tcf/Lef transcriptional activation in a mammalian system. Expression of a mutant β-catenin (β-CatS37A) in Rat-1 cells does not result in a proliferative response or a detectable change in the cytosolic β-catenin protein level. However, β-CatS37A expression in Rat-1 cells results in strong Tcf/Lef transcriptional activation, comparable to that seen in Wnt-1-expressing cells. These results suggest that Wnt-1 induction of cytosolic β-catenin may have functions in addition to Tcf/Lef transcriptional activation.

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Anagnostou, Sasha H., та Peter R. Shepherd. "Glucose induces an autocrine activation of the Wnt/β-catenin pathway in macrophage cell lines". Biochemical Journal 416, № 2 (12 листопада 2008): 211–18. http://dx.doi.org/10.1042/bj20081426.

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The canonical Wnt signalling pathway acts by slowing the rate of ubiquitin-mediated β-catenin degradation. This results in the accumulation and subsequent nuclear translocation of β-catenin, which induces the expression of a number of genes involved in growth, differentiation and metabolism. The mechanisms regulating the Wnt signalling pathway in the physiological context is still not fully understood. In the present study we provide evidence that changes in glucose levels within the physiological range can acutely regulate the levels of β-catenin in two macrophage cell lines (J774.2 and RAW264.7 cells). In particular we find that glucose induces these effects by promoting an autocrine activation of Wnt signalling that is mediated by the hexosamine pathway and changes in N-linked glycosylation of proteins. These studies reveal that the Wnt/β-catenin system is a glucose-responsive signalling system and as such is likely to play a role in pathways involved in sensing changes in metabolic status.

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