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1
Palchevska, O. L., V. V. Balatskyi, L. L. Macewicz, and O. O. Piven. "Cardiospecific deletion of β-catenin gene associated with an activity violation of signaling cascades involved in the development of myocardial hypertrophy." Visnik ukrains'kogo tovaristva genetikiv i selekcioneriv 15, no. 2 (February 28, 2018): 181–86. http://dx.doi.org/10.7124/visnyk.utgis.15.2.877.
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The aim of our study was to investigate the molecular mechanisms of hypertrophy response under cardiospecific β-catenin haploinsufficiency condition. Materials and methods. Studies were done with β-catenin condtional knockout mice (β-catflox/flox) and α-MHC-Cre-transgenic mice. To induce hypertrophy we used swimming test during 6 weeks. Using western-blot, we have analyzed the level of studied proteins. Results. It has been shown that the β-catenin haploinsufficiency is associated with increased signaling activity of MAPK, PI3-kinase-mTOR-dependent signaling cascades in both: with prolonged physical activity and without it. However, even with an increased activity of this signalling, β-catenin haploinsufficient mice expressed weaker hypertrophic response. Conclusions. The transcriptional activity of β-catenin is necessary for the proper interaction of signaling cascades during heart maturation and adaptation to stress. Keywords: β-catenin, hypertrophy, Wnt-signalling, MAPK signalling, PI3-kinase-mTOR-dependent cascade, PKA-signalling, myocardium.
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Zeller, Eva, Katharina Mock, Moritz Horn, Sabine Colnot, Michael Schwarz, and Albert Braeuning. "Dual-specificity phosphatases are targets of the Wnt/β-catenin pathway and candidate mediators of β-catenin/Ras signaling interactions." Biological Chemistry 393, no. 10 (October 1, 2012): 1183–91. http://dx.doi.org/10.1515/hsz-2012-0130.
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Abstract The Wnt/β-catenin and the Ras/mitogen-activated protein kinase (MAPK) pathways play important roles in cancer development. Both pathways have been studied discretely, but the mechanisms of possible crosstalk are still not fully understood. We have previously shown that β-catenin and MAPK signaling interfere with each other in murine liver in vivo and in vitro. Here, we show that dual specificity phosphatases (Dusps) 6 and 14, known to play an essential role in regulating MAPK pathway activity via feedback mechanisms, are up-regulated by activation of β-catenin in murine liver cells, whereas the epidermal growth factor receptor, an upstream effector in the Ras/MAPK cascade, is down-regulated by β-catenin. In addition, we identified a β-catenin-binding site within the Dusp6 promoter, which is responsible for the activation of the promoter by β-catenin signaling, and demonstrated reduced inducibility of MAPK signaling in cultured mouse hepatoma cells following β-catenin activation. Thus, β-catenin is able to inhibit activation of the Egfr/Ras/MAPK signaling cascade, both at the receptor level and by interfering with MAPK activity via Dusps.
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Cesari, Francesca. "A Rac1–JNK2–β-catenin domino cascade." Nature Reviews Molecular Cell Biology 9, no. 6 (May 9, 2008): 425. http://dx.doi.org/10.1038/nrm2412.
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Yang, Shengsen, Fei Zhou, Yi Dong, and Fei Ren. "α-Mangostin Induces Apoptosis in Human Osteosarcoma Cells Through ROS-Mediated Endoplasmic Reticulum Stress via the WNT Pathway." Cell Transplantation 30 (January 1, 2021): 096368972110350. http://dx.doi.org/10.1177/09636897211035080.
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α-mangostin has been confirmed to promote the apoptosis of MG-63 cells, but its specific pro-apoptosis mechanism in osteosarcoma (OS) remains further investigation. Here, we demonstrated that α-mangostin restrained the viability of OS cells (143B and Saos-2), but had little effect on the growth of normal human osteoblast. α-mangostin increased OS cell apoptosis by activating the caspase-3/8 cascade. Besides, α-mangostin induced endoplasmic reticulum (ER) stress and restrained the Wnt/β-catenin pathway activity. 4PBA (an ER stress inhibitor) or LiCl (an effective Wnt activator) treatment effectively hindered α-mangostin-induced apoptosis and the caspase-3/8 cascade. Furthermore, we also found that α-mangostin induced ER stress by promoting ROS production. And ER stress-mediated apoptosis caused by ROS accumulation depended on the inactivation of Wnt/β-catenin pathway. In addition, α-mangostin significantly hindered the growth of xenograft tumors, induced the expression of ER stress marker proteins and activation of the caspase-3/8 cascade, and restrained the Wnt/β-catenin signaling in vivo. In short, ROS-mediated ER stress was involved in α-mangostin triggered apoptosis, which might depended on Wnt/β-catenin signaling inactivation.
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Hendriksen, Jolita, Francois Fagotto, Hella van der Velde, Martijn van Schie, Jasprien Noordermeer, and Maarten Fornerod. "RanBP3 enhances nuclear export of active β-catenin independently of CRM1." Journal of Cell Biology 171, no. 5 (November 28, 2005): 785–97. http://dx.doi.org/10.1083/jcb.200502141.
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β-Catenin is the nuclear effector of the Wnt signaling cascade. The mechanism by which nuclear activity of β-catenin is regulated is not well defined. Therefore, we used the nuclear marker RanGTP to screen for novel nuclear β-catenin binding proteins. We identified a cofactor of chromosome region maintenance 1 (CRM1)–mediated nuclear export, Ran binding protein 3 (RanBP3), as a novel β-catenin–interacting protein that binds directly to β-catenin in a RanGTP-stimulated manner. RanBP3 inhibits β-catenin–mediated transcriptional activation in both Wnt1- and β-catenin–stimulated human cells. In Xenopus laevis embryos, RanBP3 interferes with β-catenin–induced dorsoventral axis formation. Furthermore, RanBP3 depletion stimulates the Wnt pathway in both human cells and Drosophila melanogaster embryos. In human cells, this is accompanied by an increase of dephosphorylated β-catenin in the nucleus. Conversely, overexpression of RanBP3 leads to a shift of active β-catenin toward the cytoplasm. Modulation of β-catenin activity and localization by RanBP3 is independent of adenomatous polyposis coli protein and CRM1. We conclude that RanBP3 is a direct export enhancer for β-catenin, independent of its role as a CRM1-associated nuclear export cofactor.
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Skokowa, Julia, Gunnar Cario, Lan Dan, Cornelia Zeidler, Vesna Bucan, and Karl Welte. "Proto-Oncogenes β- and γ-Catenin in Leukemogenesis in Severe Congenital Neutropenia (CN)." Blood 106, no. 11 (November 16, 2005): 94. http://dx.doi.org/10.1182/blood.v106.11.94.94.
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Abstract Severe congenital neutropenia (CN) is characterized by a “maturation arrest” of myeloid progenitors at the promyelocytic stage with few or no mature neutrophils in the bone marrow and blood. Administration of granulocyte colony-stimulating factor (G-CSF) increases neutrophil numbers in most CN patients. Approximately 10–15 % of CN patients develop AML or MDS by mechanisms that are as yet unknown. Since AML/MDS are not observed in cyclic (CyN) or idiopathic neutropenia patients treated with G-CSF, an underlying defect of hematopoiesis rather than G-CSF therapy per se predisposes to malignant transformation in CN patients. Recently, activation of Wnt/β-catenin-/γ-catenin-signaling cascade has been considered as important mechanism in the pathogenesis of AML and CML by enhancement of self-renewal activity and by increase of leukemic potential of myeloid progenitors. Moreover, stabilization of β-catenin led to an increased formation of nuclear β-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes in a variety of human malignancies. In the present study we investigated the role of β-catenin/γ-catenin in leukemogenesis in CN patients. CD33+ progenitors from CN patients expressed 2.5 times higher levels of b-catenin and 4 times higher levels of γ-catenin mRNA and protein, as assessed by quantitative real-time PCR and Western Blot analysis. Most important, in CN patients this increase was paralleled by dramatically elevated levels of activated nuclear β-catenin and intracellular γ-catenin proteins in CD33+ cells, as compared to G-CSF-treated healthy controls and CyN patients. Moreover, mRNA and protein levels of β- and γ-catenins were further increased in CD33+ cells and leukemic blasts from 4 CN patients, who developed AML. In line with high β-/γ-catenins levels, expression of target genes c-jun, fra-1 and PPARD was also up-regulated. There was no correlation between activated Wnt/β-/γ-catenin signaling system and mutations in G-CSF receptor, or ELA2 gene. To investigate the mechanisms of stabilization and increased nuclear translocation of b-catenin, we analyzed the components of b-catenin-degradation multiprotein complex, which contains of Axin, GSK3β, and APC. No differences in expression of Axin, GSK3β and APC as well as in phosphorylation status of GSK3β in CD33+ cells from CN patients and controls were observed. Sequence analysis revealed no mutations in β-catenin gene. Furthermore we analysed the expression of E-cadherin, which forms the transmembrane core of adherent junctions by bridging to β-catenin and therefore modulates its subcellular localization and nuclear translocation. E-cadherin mRNA and protein expression was dramatically downregulated in CD33+ myeloid progenitors from CN patients, in comparison to G-CSF treated healthy controls. Moreover, confocal microscopy revealed very low levels of co-localized E-cadherin and β-catenin in CD33+ cells from CN patients. Therefore, we hypothesize that loss of E-cadherin expression results in nuclear accumulation of β-catenin and activation of its downstream signaling in CN. Taken together, high expression of the proto-oncogenes β- and γ-catenins and nuclear accumulation of β-catenin could contribute to the malignant transformation of myelopoiesis in CN.
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Kumar, Amit, Ravindra B. Chalamalasetty, Mark W. Kennedy, Sara Thomas, Shreya N. Inala, Robert J. Garriock, and Terry P. Yamaguchi. "Zfp703 Is a Wnt/β-Catenin Feedback Suppressor Targeting the β-Catenin/Tcf1 Complex." Molecular and Cellular Biology 36, no. 12 (April 18, 2016): 1793–802. http://dx.doi.org/10.1128/mcb.01010-15.
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The Wnt/β-catenin signaling pathway controls embryonic development and adult stem cell maintenance through the regulation of transcription. Failure to downregulate Wnt signaling can result in embryonic malformations and cancer, highlighting the important role of negative regulators of the pathway. The Wnt pathway activates several negative feedback targets, including axin2 and Dkk1, that function at different levels of the signaling cascade; however, none have been identified that directly target active β-catenin/Tcf1 transcriptional complexes. We show thatZfp703is a Wnt target gene that inhibits Wnt/β-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation in embryonic stem cells. Zfp703 binds directly to Tcf1 to inhibit β-catenin/Tcf1 complex formation and does so independently of the Groucho/Tle transcriptional corepressor. We propose that Zfp703 is a novel feedback suppressor of Wnt/β-catenin signaling that functions by inhibiting the association of β-catenin with Tcf1 on Wnt response elements in target gene enhancers.
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Wang, Xiaohong, Neeta Adhikari, Qinglu Li, and Jennifer L. Hall. "LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 6 (December 2004): H2376—H2383. http://dx.doi.org/10.1152/ajpheart.01173.2003.
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Initial studies have established expression of low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) in vascular smooth muscle cells (VSMCs). We hypothesized that LRP6 is a critical mediator governing the regulation of the canonical Wnt/β-catenin/T cell factor 4 (Tcf-4) cascade in the vasculature. This hypothesis was based on our previous work demonstrating a role for the β-catenin/Tcf-4 pathway in vascular remodeling as well as work in other cell systems establishing a role for LRP family members in the Wnt cascade. In line with our hypothesis, LRP6 upregulation significantly increased Wnt-1-induced Tcf activation. Moreover, a dominant interfering LRP6 mutant lacking the carboxyl intracellular domain (LRP6ΔC) abolished Tcf activity. LRP6-induced stimulation of Tcf was blocked in VSMCs harboring constitutive expression of a dominant negative Tcf-4 transgene lacking the β-catenin binding domain, suggesting that LRP6-induced activation of Tcf was mediated through a β-catenin-dependent signal. Expression of the dominant interfering LRP6ΔC transgene was sufficient to abolish the Wnt-induced survival as well as cyclin D1 activity and cell cycle progression. In conclusion, these findings provide the first evidence of a role for an LDL receptor-related protein in the regulation of VSMC proliferation and survival through the evolutionary conserved Wnt signaling cascade.
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HAGEN, Thilo, Jaswinder K. SETHI, Neale FOXWELL, and Antonio VIDAL-PUIG. "Signalling activity of beta-catenin targeted to different subcellular compartments." Biochemical Journal 379, no. 2 (April 15, 2004): 471–77. http://dx.doi.org/10.1042/bj20031749.
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β-Catenin plays a dual role as an adhesion molecule in adherens junctions at the plasma membrane and as a key intermediate in the canonical Wnt signalling pathway. The cytosolic soluble pool of β-catenin, involved in the transmission of the Wnt signal, is normally subjected to rapid protein degradation. On activation of the Wnt cascade, β-catenin becomes stabilized and then translocates into the nucleus where it co-activates transcription factors of the TCF (T-cell factor)/LEF (lymphoid enhancer factor) family. The expression of plasma membrane-targeted forms of β-catenin has been shown to also activate TCF/LEF-dependent transcription and different mechanisms have been put forward. In the present study, we have undertaken a systematic analysis of the signalling capability of non-degradable forms of β-catenin targeted to different cellular compartments. β-Catenin targeted to the plasma membrane activated transcription to a greater extent compared with non-targeted β-catenin, and led to a marked stabilization of cytosolic soluble β-catenin. These effects were independent of the competition with endogenous β-catenin for binding to E-cadherin at the plasma membrane, since targeting non-degradable β-catenin to other cellular compartments, i.e. the outer mitochondrial membrane and the endoplasmic reticulum membrane, also resulted in the accumulation of cytosolic wild-type β-catenin and activation of β-catenin-dependent signalling. In contrast, nuclear-targeted β-catenin was without significant effect on cytosolic wild-type β-catenin and did not activate transcription. Our results suggest that cytosolic accumulation of β-catenin is a prerequisite for the activation of TCF/LEF-dependent transcription in the nucleus.
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Ishitani, Tohru, Satoshi Kishida, Junko Hyodo-Miura, Naoto Ueno, Jun Yasuda, Marian Waterman, Hiroshi Shibuya, Randall T. Moon, Jun Ninomiya-Tsuji, and Kunihiro Matsumoto. "The TAK1-NLK Mitogen-Activated Protein Kinase Cascade Functions in the Wnt-5a/Ca2+ Pathway To Antagonize Wnt/β-Catenin Signaling." Molecular and Cellular Biology 23, no. 1 (January 1, 2003): 131–39. http://dx.doi.org/10.1128/mcb.23.1.131-139.2003.
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ABSTRACT Wnt signaling controls a variety of developmental processes. The canonical Wnt/β-catenin pathway functions to stabilize β-catenin, and the noncanonical Wnt/Ca2+ pathway activates Ca2+/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca2+ pathway activated by Wnt-5a antagonizes the Wnt/β-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/β-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (β2AR-Rfz-2) containing the ligand-binding and transmembrane segments from the β2-adrenergic receptor (β2AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the β-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits β-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca2+ pathway and antagonizes canonical Wnt/β-catenin signaling.
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Langhammer, Tina-Susann, Catrin Roolf, Saskia Krohn, Christin Kretzschmar, Rayk Huebner, Arndt Rolfs, Mathias Freund, and Christian Junghanss. "PI3K/Akt Signaling Interacts With Wnt/β-Catenin Signaling But Does Not Induce An Accumulation Of β-Catenin In The Nucleus Of Acute Lymphoblastic Leukemia Cell Lines." Blood 122, no. 21 (November 15, 2013): 4886. http://dx.doi.org/10.1182/blood.v122.21.4886.4886.
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Abstract Signaling pathways play essential roles in biological processes as development, cell proliferation and homeostasis. The accurate modulation of signaling pathways, their adapted interaction and their time- and tissue-specific adjusted regulation are required for normal cell development. PI3K/Akt and Wnt/β-Catenin signaling pathways act as key regulators in cell proliferation, differentiation and growth. Both signaling pathways include GSK3β as a common protein, which may mediate an interaction and cross-talk between the pathways. Aberrant activation of PI3K/Akt signaling has been linked to different types of leukemia while Wnt/β-Catenin signaling is known to be deregulated in some solid tumors. However, a potential role of Wnt/β-Catenin signaling for pathogenesis of acute lymphoblastic leukemia (ALL) has not yet been analyzed. In our study we analyzed both signaling pathways in different B- and T-ALL cell lines (RS4;11, SEM, REH, CEM, Jurkat, MOLT-4), thereby focusing mainly on their potential interaction via the protein GSK3β. Western Blot experiments were performed to evaluate the expression of specific PI3K/Akt and Wnt/β-Catenin key proteins. To evaluate the activation status of Wnt signaling immunofluorescence and protein fractionation experiments were performed, analyzing the activation linked nucleic localization of β-Catenin. The effect of pathway activation and inhibition on cell proliferation via chemical compounds was analyzed by WST-1 test. High pAkt levels were detected in B-ALL cell line SEM and T-ALL cell line CEM, indicating a hyperactive PI3K/Akt signaling, whereas other analyzed cell lines diplayed lower pAkt status. Among all cell lines analyzed SEM and CEM also showed the highest cytoplasmic β-Catenin levels, indicating a direct interaction of both signaling pathways. However, immunofluorescence and fractionation experiments revealed that a translocation of β-Catenin into the nucleus did not occur. To further investigate the role and interaction of PI3K/Akt and Wnt/β-Catenin signaling, pathway inhibiting and stimulating experiments were performed. Treatment of cells with Wnt3a led to activation of the Wnt/β-Catenin signaling cascade, characterized by nuclear β-Catenin accumulation. Inhibition of cell proliferation was detected after treatment with high concentrations Wnt3a (≥ 500 ng/ml). PI3K inhibition by LY294002 led to decreased phosphorylation of GSK3β at Ser9 and an increased decay of β-Catenin. Stimulation of PI3K/Akt signaling using activating ligand FLT3L induced GSK3β phosphorylation at Ser9 and accumulation of cytoplasmic β-Catenin. However a translocation of β-Catenin into the nucleus seems not to occur. In summary our results indicate that PI3K/Akt and Wnt/β-Catenin signaling can interact through their common protein GSK3β, but stimulation of the PI3K/Akt signaling pathway by addition of PI3K/Akt specific activators does not fully activate Wnt/β-Catenin signaling in ALL cells. Complete activation of the Wnt cascade characterized by translocation of β-Catenin into the nucleus can only be induced by use of specific Wnt effectors. Disclosures: No relevant conflicts of interest to declare.
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Matsubara, Shyuichiro, and Masayuki Ozawa. "Expression of α-catenin in α-catenin–deficient cells increases resistance to sphingosine-induced apoptosis." Journal of Cell Biology 154, no. 3 (August 6, 2001): 573–84. http://dx.doi.org/10.1083/jcb.200103097.
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α-Catenin, an intracellular protein, associates with the COOH-terminal region of cadherin cell adhesion molecules through interactions with either β-catenin or γ-catenin (plakoglobin). The full activity of cadherins requires a linkage to the actin cytoskeleton mediated by catenins. We transfected α-catenin–deficient colon carcinoma cells with a series of α-catenin constructs to determine that α-catenin expression increases the resistance to apoptosis induced by sphingosine. Two groups of constructs, containing deletions in either the middle segment of the molecule or the COOH terminus, induced morphological changes, cell compaction, and decreases in cell death. In α-catenin–expressing cells, inhibition of cadherin cell adhesion by treatment with anti–E-cadherin antibodies did not decrease the cells viability. α-Catenin expression partially suppressed the downregulation of Bcl-xL and the activation of caspase 3. Expression of p27kip1 protein, an inhibitor of cyclin-dependent kinases, was increased by α-catenin expression in low density cell cultures. The increased levels of p27kip1 correlated with both increased resistance to cell death and morphological changes in transfectants containing deletion mutants. Transfection-mediated upregulation of p27kip1 decreases sphingosine-induced cell death in α-catenin–deficient cells. We postulate that α-catenin mediates transduction of signals from the cadherin–catenin complex to regulate the apoptotic cascade via p27kip1.
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Quarta, Santina, Andrea Cappon, Cristian Turato, Mariagrazia Ruvoletto, Stefania Cannito, Gianmarco Villano, Alessandra Biasiolo, et al. "SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness." Biology 12, no. 6 (May 26, 2023): 771. http://dx.doi.org/10.3390/biology12060771.
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Abnormal activation of the Wnt-β-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-β-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear β-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of β-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose–dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members.
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Machado, Tanise Policarpo, Josiane Borges Stolfo, Márcio Machado Costa, Rubens Rodriguez, and Adriana Costa Da Motta. "Is there a relationship between the expression of β-catenin and Ki-67 in canine melanocytic neoplasms?" Brazilian Journal of Development 8, no. 9 (September 6, 2022): 61247–56. http://dx.doi.org/10.34117/bjdv8n9-058.
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An immunohistochemical evaluation of 26 cutaneous and oral benign and malignant canine melanocytic neoplasms was performed to identify a possible relationship between the expression of the β-catenin molecule with cell proliferation using Ki-67 expression. This molecule is a component of the Wnt/β-catenin signalling pathway, which causes a cascade of intracellular events that activate transduction genes and nuclear transcription. The microscopic evaluation was performed considering the β-catenin labelling site (cytoplasmic, nuclear or mixed). The mitotic index was evaluated by the expression of Ki-67 in 10 high power fields (HPF) (400x). Statistically significant difference was neither detected between the β-catenin labelling sites and the various neoplasms, nor a correlation between the β-catenin molecule and the cell proliferation marker Ki-67 in the oral or cutaneous, benign or malignant neoplasms. Our study brings interesting findings and points to future research on this topic, especially with established variables in the clinical, pathological and immunohistochemical fields.
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Dorfman, Tatiana, Yulia Pollak, Rima Sohotnik, Arnold G. Coran, Jacob Bejar, and Igor Sukhotnik. "Enhanced intestinal epithelial cell proliferation in diabetic rats correlates with β-catenin accumulation." Journal of Endocrinology 226, no. 3 (June 25, 2015): 135–43. http://dx.doi.org/10.1530/joe-14-0725.
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The Wnt/β-catenin signaling cascade is implicated in the control of stem cell activity, cell proliferation, and cell survival of the gastrointestinal epithelium. Recent evidence indicates that the Wnt/β-catenin pathway is activated under diabetic conditions. The purpose of this study was to evaluate the role of Wnt/β-catenin signaling during diabetes-induced enteropathy in a rat model. Male rats were divided into three groups: control rats received injections of vehicle; diabetic rats received injections of one dose of streptozotocin (STZ); and diabetic–insulin rats received injections of STZ and were treated with insulin given subcutaneously at a dose of 1 U/kg twice daily. Rats were killed on day 7. Wnt/β-catenin-related genes and expression of proteins was determined using real-time PCR, western blotting, and immunohistochemistry. Among 13 genes identified by real-time PCR, seven genes were upregulated in diabetic rats compared with control animals including the target genes c-Myc and Tcf4. Diabetic rats also showed a significant increase in β-catenin protein compared with control animals. Treatment of diabetic rats attenuated the stimulating effect of diabetes on intestinal cell proliferation and Wnt/β-catenin signaling. In conclusion, enhanced intestinal epithelial cell proliferation in diabetic rats correlates with β-catenin accumulation.
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Reis, Marco, Cathrin J. Czupalla, Nicole Ziegler, Kavi Devraj, Jenny Zinke, Sascha Seidel, Rosario Heck, et al. "Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression." Journal of Experimental Medicine 209, no. 9 (August 20, 2012): 1611–27. http://dx.doi.org/10.1084/jem.20111580.
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Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.
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Crino, Peter B. "Molecular Pathogenesis of Focal Cortical Dysplasia and Hemimegalencephaly." Journal of Child Neurology 19, no. 3 (March 2004): 330–36. http://dx.doi.org/10.1177/08830738040190031101.
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My laboratory recently demonstrated that there is selective expression of phosphoribosomal S6 protein in balloon cells in focal cortical dysplasia and hemimegalencephaly but no expression of the upstream kinase, phospho-p70S6 kinase. Two proteins activated by phospho-p70S6 kinase, phospho-STAT3 and phospho-4EBP1, were not detected in balloon cells. Using complementary DNA arrays in hemimegalencephaly specimens, we found increased expression of cyclin D1 and c-myc messenger ribonucleic acids (RNAs). Expression of cyclin D1 and c-myc genes is transcriptionally activated by βcatenin. Western analysis demonstrated increased levels of nonphosphorylated β-catenin in hemimegalencephalic cortex. Reduced levels of Ser33, Ser37, and Thr41 phospho-β-catenin, sites known to be phosphorylated by glycogen synthase kinase 3 and to be essential for β-catenin inactivation, were detected in hemimegalencephaly. Enhanced transcription of cyclin D1 and c-myc messenger RNAs, increased transcriptionally active β-catenin, and decreased Ser33/Ser37/Thr41 phospho-β-catenin suggest activation of the Wnt-1/β-catenin cascade in hemimegalencephaly, which can lead to aberrant cell proliferation and hemispheric enlargement during brain development. Enhanced activation of phospho-S6 and β-catenin suggests two converging cell pathways that can be pivotal in the pathogenesis of focal cortical dysplasia and hemimegalencephaly. ( J Child Neurol 2005;20:330—336).
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Grishanova, Alevtina Y., Lyubov S. Klyushova, and Maria L. Perepechaeva. "AhR and Wnt/β-Catenin Signaling Pathways and Their Interplay." Current Issues in Molecular Biology 45, no. 5 (May 2, 2023): 3848–76. http://dx.doi.org/10.3390/cimb45050248.
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As evolutionarily conserved signaling cascades, AhR and Wnt signaling pathways play a critical role in the control over numerous vital embryonic and somatic processes. AhR performs many endogenous functions by integrating its signaling pathway into organ homeostasis and into the maintenance of crucial cellular functions and biological processes. The Wnt signaling pathway regulates cell proliferation, differentiation, and many other phenomena, and this regulation is important for embryonic development and the dynamic balance of adult tissues. AhR and Wnt are the main signaling pathways participating in the control of cell fate and function. They occupy a central position in a variety of processes linked with development and various pathological conditions. Given the importance of these two signaling cascades, it would be interesting to elucidate the biological implications of their interaction. Functional connections between AhR and Wnt signals take place in cases of crosstalk or interplay, about which quite a lot of information has been accumulated in recent years. This review is focused on recent studies about the mutual interactions of key mediators of AhR and Wnt/β-catenin signaling pathways and on the assessment of the complexity of the crosstalk between the AhR signaling cascade and the canonical Wnt pathway.
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Kim, Jaeyoon, Jae Young Shin, Yun-Ho Choi, Nae Gyu Kang, and Sanghwa Lee. "Anti-Hair Loss Effect of Adenosine Is Exerted by cAMP Mediated Wnt/β-Catenin Pathway Stimulation via Modulation of Gsk3β Activity in Cultured Human Dermal Papilla Cells." Molecules 27, no. 7 (March 28, 2022): 2184. http://dx.doi.org/10.3390/molecules27072184.
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In the present study, we investigated the molecular mechanisms of adenosine for its hair growth promoting effect. Adenosine stimulated the Wnt/β-catenin pathway by modulating the activity of Gsk3β in cultured human dermal papilla cells. It also activated adenosine receptor signaling, increasing intracellular cAMP level, and subsequently stimulating the cAMP mediated cellular energy metabolism. The phosphorylation of CREB, mTOR, and GSK3β was increased. Furthermore, the expression of β-catenin target genes such as Axin2, Lef1, and growth factors (bFGF, FGF7, IGF-1) was also enhanced. The inhibitor study data conducted in Wnt reporter cells and in cultured human dermal papilla cells demonstrated that adenosine stimulates Wnt/β-catenin signaling through the activation of the adenosine receptor and Gsk3β plays a critical role in transmitting the signals from the adenosine receptor to β-catenin, possibly via the Gαs/cAMP/PKA/mTOR signaling cascade.
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Wang, Zhongyuan, Bo Li, Liang Zhou, Shubin Yu, Zijie Su, Jiaxing Song, Qi Sun, et al. "Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells." Proceedings of the National Academy of Sciences 113, no. 46 (October 31, 2016): 13150–55. http://dx.doi.org/10.1073/pnas.1616336113.
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Prodigiosin, a natural red pigment produced by numerous bacterial species, has exhibited promising anticancer activity; however, the molecular mechanisms of action of prodigiosin on malignant cells remain unclear. Aberrant activation of the Wnt/β-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/β-catenin pathway. Prodigiosin blocked Wnt/β-catenin signaling by targeting multiple sites of this pathway, including the low-density lipoprotein-receptor-related protein (LRP) 6, Dishevelled (DVL), and glycogen synthase kinase-3β (GSK3β). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3β and suppressed β-catenin–stimulated Wnt target gene expression, including expression of cyclin D1. In MDA-MB-231 breast cancer xenografts and MMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3β, active β-catenin, and cyclin D1. Through its ability to inhibit Wnt/β-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.
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Failor, Kim L., Yelena Desyatnikov, Lindsay A. Finger, and Gary L. Firestone. "Glucocorticoid-Induced Degradation of Glycogen Synthase Kinase-3 Protein Is Triggered by Serum- and Glucocorticoid-Induced Protein Kinase and Akt Signaling and Controls β-Catenin Dynamics and Tight Junction Formation in Mammary Epithelial Tumor Cells." Molecular Endocrinology 21, no. 10 (October 1, 2007): 2403–15. http://dx.doi.org/10.1210/me.2007-0143.
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Abstract Glucocorticoid hormones stimulate adherens junction and tight junction formation in Con8 mammary epithelial tumor cells and induce the production of a stable nonphosphorylated β-catenin protein localized exclusively to the cell periphery. Glycogen synthase kinase-3 (GSK3) phosphorylation of β-catenin is known to trigger the degradation of this adherens junction protein, suggesting that steroid-activated cascades may be targeting this protein kinase. We now demonstrate that treatment with the synthetic glucocorticoid dexamethasone induces the ubiquitin-26S proteasome-mediated degradation of GSK3 protein with no change in GSK3 transcript levels. In transfected cells, deletion of the N-terminal nine amino acids or mutation of the serine-9 phosphorylation site on GSK3-β prevented its glucocorticoid-induced degradation. Expression of stabilized GSK3 mutant proteins ablated the glucocorticoid-induced tight junction sealing and resulted in production of a nonphosphorylated β-catenin that localizes to both the nucleus and the cell periphery in steroid-treated cells. Serine-9 on GSK3 can be phosphorylated by Sgk (serum- and glucocorticoid-induced protein kinase) and by Akt. Expression of dominant-negative forms of either Sgk- or Akt-inhibited glucocorticoid induced GSK3 ubiquitination and degradation and disrupted the dexamethasone-induced effects on β-catenin dynamics. Furthermore, the steroid-induced tight junction sealing is attenuated in cells expressing dominant-negative forms of either Sgk or Akt, although the effect of blunting Sgk signaling was significantly greater. Taken together, we have uncovered a new cellular cascade in which Sgk and Akt trigger the glucocorticoid-regulated phosphorylation, ubiquitination, and degradation of GSK3, which alters β-catenin dynamics, leading to the formation of adherens junctions and tight junction sealing.
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Banerjee, Anwesha, Mamta Chawla-Sarkar, and Anupam Mukherjee. "Rotavirus-Mediated Suppression of miRNA-192 Family and miRNA-181a Activates Wnt/β-Catenin Signaling Pathway: An In Vitro Study." Viruses 14, no. 3 (March 9, 2022): 558. http://dx.doi.org/10.3390/v14030558.
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The significance of the Wnt/β-catenin signaling cascade in Rotavirus (RV) infection has not been elucidated. In this study, we attempt to elucidate the importance of the Wnt/β-catenin pathway in the RV pathogenesis and investigate a miRNA-mediated approach to regulate the pathway to repress the RV infection in the host. The regulation of the Wnt signaling pathway in terms of β-catenin accumulation and activation was analyzed by Western blotting and Confocal imaging analysis. The expression levels of miR-192 family members and miR-181a were enquired into using qPCR assays, whereas their targets in the Wnt pathway were confirmed using the Luciferase Reporter Assays. Members of the miR-192 family and miR-181a, which target the components of the pathway, were also found to be considerably decreased in expression during RV infection. Ectopic expression of these miRNAs could restrict the RV pathogenesis by targeting the intermediates of the Wnt signaling pathway. The miR-192 family and miR-181a were capable of suppressing the RV infection via targeting of the Wnt/β-catenin pathway. The study not only highlights the role of the Wnt signaling cascade in RV infection but also suggests that miRNAs can synergistically decrease RV replication by a significant amount. Thus, the miR-192 family and miR-181a present themselves as prospective antivirals against RV infection.
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Rao, A. S., N. Kremenevskaja, J. Resch, and G. Brabant. "Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/β-catenin signalling." European Journal of Endocrinology 153, no. 6 (December 2005): 929–38. http://dx.doi.org/10.1530/eje.1.02038.
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Background: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/β-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3β inhibition, which in turn stabilizes cytosolic free β-catenin. Here we investigated the potential modulation of Wnt/β-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. Methods: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. Results: LiCl dose-dependently inhibited GSK-3β, stabilized free β-catenin and inhibited β-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by β-catenin, since nuclear β-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/β-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/β-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. Conclusion: Our data indicate that Wnt/β-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.
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Rheinschmidt, Shelby, Trason Thode, Samuel Sampson, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Ryan Rodriguez del Villar, et al. "Abstract 2567: Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2567. http://dx.doi.org/10.1158/1538-7445.am2022-2567.
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Abstract Purpose: Canonical Wnt signaling is a key cascade in regulating development and stemness, however it can become dysregulated and tightly associated with oncogenesis. In human cancers, Wnt/β-catenin signaling is highly activated due to mutations of members associated with the pathway such as adenomatous polyposis coli (APC) and β-catenin. Transducin β-like protein 1 (TBL1) and highly related TBLR1, form a complex with β-catenin facilitating the translocation of β-catenin to the nucleus. The formation of this complex protects β-catenin from degradation by SIAH-1 ubiquitinase and aids β-catenin binding to TCF/LEF transcription factors to transcribe downstream Wnt target genes. We recently reported that the destruction of the TBL1/β-catenin complex using a small molecule results in ubiquitination of β-catenin and inhibition of downstream signaling. As an alternative approach, we designed a series of novel peptides to interfere with binding of β-catenin with TBL1. Methods: Homologous competitive ELISA and thermal shift assays were performed to identify potential peptides that were able to displace β-catenin from TBL1. Additionally, we evaluated the ability of the peptides to disrupt the TBL1/β-catenin complex by performing pull-down assays and monitored the levels of β-catenin ubiquitination in response to peptide treatment in colon cell lines. To assess the levels of TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway, we performed TOPFlash assays in Wnt-activated cells transfected with plasmids for peptide expression. Results: Our preliminary results identified a set of peptides that efficiently displaces β-catenin from TBL1. Homologous competitive ELISA showed that the peptides were able to displace β-catenin from TBL1 in a dose dependent manner. The top five peptide hits were then tested for their ability to inhibit Wnt signaling using the TOPFlash assay. Among these, one peptide in particular showed high efficiency in inhibiting TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway. Our study suggests that β-catenin therapeutic peptides may represent a new and exciting approach for Wnt driven cancer therapy. Citation Format: Shelby Rheinschmidt, Trason Thode, Samuel Sampson, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Ryan Rodriguez del Villar, Mohan Kaadige, Anton Zernov, Marcelle Machluf, Raffaella Soldi, Sunil Sharma. Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2567.
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Jiao, Zixue, Hao Chai, Shendong Wang, Chunguang Sun, Qun Huang, and Wei Xu. "SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis." Journal of Molecular Medicine 101, no. 5 (May 2023): 607–20. http://dx.doi.org/10.1007/s00109-023-02319-2.
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Abstract The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST gene and its synthetic protein, sclerostin, are hallmarks of osteocytes. According to our previous findings, blocking SOST induces bone formation and protects against bone loss and deformation caused by titanium (Ti) particles by activating the Wnt/β-catenin cascade. Although SOST has been shown to influence osteoblasts, its ability to control wear-particle-induced osteolysis via targeting osteoclasts remains unclear. Mice were subjected to development of a cranial osteolysis model. Micro CT, HE staining, and TRAP staining were performed to evaluate bone loss in the mouse model. Bone marrow-derived monocyte-macrophages (BMMs) made from the C57BL/6 mice were exposed to the medium of MLO-Y4 (co-cultured with Ti particles) to transform them into osteoclasts. Bioinformatics methods were used to predict and validate the interaction among SOST, Wnt/β-catenin, RANKL/OPG, TNF-α, and IL-6. Local bone density and bone volume improved after SOST inhibition, both the number of lysis pores and the rate of skull erosion decreased. Histological research showed that β-catenin and OPG expression were markedly increased after SOST inhibition, whereas TRAP and RANKL levels were markedly decreased. In-vitro, Ti particle treatment elevated the expression of sclerostin, suppressed the expression of β-catenin, and increased the RANKL/OPG ratio in the MLO-Y4 cell line. TNF-α and IL-6 also elevated after treatment with Ti particles. The expression levels of NFATc1, CTSK, and TRAP in osteoclasts were significantly increased, and the number of positive cells for TRAP staining was increased. Additionally, the volume of bone resorption increased at the same time. In contrast, when SOST expression was inhibited in the MLO-Y4 cell line, these effects produced by Ti particles were reversed. All the results strongly show that SOST inhibition triggered the osteocyte Wnt/β-catenin signaling cascade and prevented wear particle-induced osteoclastogenesis, which might reduce periprosthetic osteolysis. Key messages SOST is a molecular regulator in maintaining bone homeostasis. SOST plays in regulating bone homeostasis through the Wnt/β-catenin signaling pathway. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis.
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Mulholland, David J., Shoukat Dedhar, Gerhard A. Coetzee, and Colleen C. Nelson. "Interaction of Nuclear Receptors with the Wnt/β-Catenin/Tcf Signaling Axis: Wnt You Like to Know?" Endocrine Reviews 26, no. 7 (August 26, 2005): 898–915. http://dx.doi.org/10.1210/er.2003-0034.
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The cross-regulation of Wnt/β-catenin/Tcf ligands, kinases, and transcription factors with members of the nuclear receptor (NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis, and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/β-catenin modulation of NRs (theme I), and ligand-dependent NR inhibition of the Wnt/β-catenin/Tcf cascade (theme II). β-Catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). β-Catenin acts as a coactivator of AR transcription and is also involved in cotrafficking, increasing cell proliferation, and prostate pathogenesis. T cell factor, a transcriptional mediator of β-catenin and AR, engages in a dynamic reciprocity of nuclear β-catenin, p300/CREB binding protein, and transcriptional initiation factor 2/GC receptor-interaction protein, thereby facilitating hormone-dependent coactivation and transrepression. β-Catenin responds in an equally dynamic manner with other NRs, including the retinoic acid (RA) receptor (RAR), vitamin D receptor (VDR), glucocorticoid receptor (GR), progesterone receptor, thyroid receptor (TR), estrogen receptor (ER), and peroxisome proliferator-activated receptor (PPAR). The NR ligands, vitamin D3, trans/cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/β-catenin/Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. β-Catenin has been intensively studied in colorectal cancer; however, it is now evident that β-catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross-regulation of AR and Wnt/β-catenin/Tcf but will also consider the dynamic manner in which RAR/RXR, GR, TR, VDR, ER, and PPAR modulate canonical Wnt signaling. Although many commonalities exist by which NRs interact with the Wnt/β-catenin signaling pathway, striking cell line and tissue-specific differences require deciphering and application to endocrine pathology.
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Sarkar, Sayantani, Chandan Mandal, Rajender Sangwan, and Chitra Mandal. "Coupling G2/M arrest to the Wnt/β-catenin pathway restrains pancreatic adenocarcinoma." Endocrine-Related Cancer 21, no. 1 (February 2014): 113–25. http://dx.doi.org/10.1530/erc-13-0315.
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β-catenin plays a pivotal role in organogenesis and oncogenesis. Alterations in β-catenin expression are common in pancreatic cancer, which is an extremely aggressive malignancy with a notably poor prognosis. In this report, we analyzed the apoptotic activity of withanolide-D (witha-D), a steroidal lactone that was purified from an Indian medicinal plant,Withania somnifera, and its underlying mechanism of action. Witha-D induced apoptosis in pancreatic ductal adenocarcinoma cells by prompting cell-cycle arrest at the G2/M phase. This lactone abrogated β-catenin signaling in these cells regardless of disease grade, mutational status, and gemcitabine sensitivity. Witha-D also upregulated E-cadherin in most cells, thereby supporting the inversion of the epithelial–mesenchymal transition. Furthermore, the Akt/Gsk3β kinase cascade was identified as a critical mediator of G2/M regulation and β-catenin signaling. Witha-D deactivated Akt, which failed to promote Gsk3β deactivation phosphorylation. Consequently, activated Gsk3β facilitated β-catenin destruction in pancreatic carcinoma cells. The knockdown of Chk1 and Chk2 further activated Akt and reversed the molecular signal. Taken together, the results of the current study represent the first evidence of β-catenin signal crosstalk during the G2/M phase by functionally inactivating Akt via witha-D treatment in pancreatic cancer cells. In conclusion, this finding suggests the potential identification of a new lead molecule in the treatment of pancreatic adenocarcinoma.
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Torres, Monica A., Hagit Eldar-Finkelman, Edwin G. Krebs, and Randall T. Moon. "Regulation of Ribosomal S6 Protein Kinase-p90rsk, Glycogen Synthase Kinase 3, and β-Catenin in Early Xenopus Development." Molecular and Cellular Biology 19, no. 2 (February 1, 1999): 1427–37. http://dx.doi.org/10.1128/mcb.19.2.1427.
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ABSTRACT β-Catenin is a multifunctional protein that binds cadherins at the plasma membrane, HMG box transcription factors in the nucleus, and several cytoplasmic proteins that are involved in regulating its stability. In developing embryos and in some human cancers, the accumulation of β-catenin in the cytoplasm and subsequently the nuclei of cells may be regulated by the Wnt-1 signaling cascade and by glycogen synthase kinase 3 (GSK-3). This has increased interest in regulators of both GSK-3 and β-catenin. Searching for kinase activities able to phosphorylate the conserved, inhibitory-regulatory GSK-3 residue serine 9, we found p90 rsk to be a potential upstream regulator of GSK-3. Overexpression of p90 rsk in Xenopus embryos leads to increased steady-state levels of total β-catenin but not of the free soluble protein. Instead, p90 rsk overexpression increases the levels of β-catenin in a cell fraction containing membrane-associated cadherins. Consistent with the lack of elevation of free β-catenin levels, ectopic p90 rsk was unable to rescue dorsal cell fate in embryos ventralized by UV irradiation. We show that p90 rsk is a downstream target of fibroblast growth factor (FGF) signaling during early Xenopus development, since ectopic FGF signaling activates both endogenous and overexpressed p90 rsk . Moreover, overexpression of a dominant negative FGF receptor, which blocks endogenous FGF signaling, leads to decreased p90 rsk kinase activity. Finally, we report that FGF inhibits endogenous GSK-3 activity inXenopus embryos. We hypothesize that FGF and p90 rsk play heretofore unsuspected roles in modulating GSK-3 and β-catenin.
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Wang, Cong, Huiming Zhu, Zhaorui Sun, Zou Xiang, Yuanyuan Ge, Can Ni, Zhaowen Luo, Weiping Qian, and Xiaodong Han. "Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury." American Journal of Physiology-Cell Physiology 307, no. 3 (August 1, 2014): C234—C244. http://dx.doi.org/10.1152/ajpcell.00366.2013.
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Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/β-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of β-catenin and suppression of the Wnt/β-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/β-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/β-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/β-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking.
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Koni, Malvina, Veronica Pinnarò, and Maria Felice Brizzi. "The Wnt Signalling Pathway: A Tailored Target in Cancer." International Journal of Molecular Sciences 21, no. 20 (October 18, 2020): 7697. http://dx.doi.org/10.3390/ijms21207697.
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Cancer is one of the greatest public health challenges. According to the World Health Organization (WHO), 9.6 million cancer deaths have been reported in 2018. The most common cancers include lung, breast, colorectal, prostate, skin (non-melanoma) and stomach cancer. The unbalance of physiological signalling pathways due to the acquisition of mutations in tumour cells is considered the most common cancer driver. The Wingless-related integration site (Wnt)/β-catenin pathway is crucial for tissue development and homeostasis in all animal species and its dysregulation is one of the most relevant events linked to cancer development and dissemination. The canonical and the non-canonical Wnt/β-catenin pathways are known to control both physiological and pathological processes, including cancer. Herein, the impact of the Wnt/β-catenin cascade in driving cancers from different origin has been examined. Finally, based on the impact of Extracellular Vesicles (EVs) on tumour growth, invasion and chemoresistance, and their role as tumour diagnostic and prognostic tools, an overview of the current knowledge linking EVs to the Wnt/β-catenin pathway is also discussed.
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Shang, Zesen, Jiao Zhao, Qi Zhang, Cheng Cao, Shanshan Tian, Kai Zhang, Ling Liu, Lei Shi, Na Yu, and Shangda Yang. "USP9X-mediated deubiquitination of B-cell CLL/lymphoma 9 potentiates Wnt signaling and promotes breast carcinogenesis." Journal of Biological Chemistry 294, no. 25 (May 9, 2019): 9844–57. http://dx.doi.org/10.1074/jbc.ra119.007655.
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Hyperactivation of the canonical Wnt-signaling pathway is a prominent feature of a number of human malignancies. Transcriptional activation of this signaling cascade depends on the formation of the β-catenin–B-cell CLL/lymphoma 9 (BCL9)–pygopus (PYGO) family plant homeodomain finger 1 complex, yet how the assembly of this complex is regulated remains to be investigated. Here, using MCF-7, HeLa, HEK293T, MDA–MB-231, and Sf9 cells, along with immunoblotting and immunofluorescence, nano-HPLC–MS/MS, deubiquitination, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assays, we report that BCL9 physically associates with a protein deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), and that USP9X removes Lys-63–linked polyubiquitin on Lys-212 of BCL9. Importantly, the USP9X-mediated BCL9 deubiquitination facilitated the formation of the β-catenin–BCL9–PYGO complex, thereby potentiating the transcriptional activation of Wnt/β-catenin target genes. We also show that USP9X-mediated BCL9 deubiquitination promotes the proliferation and invasion of breast cancer cells. Together, these results uncover USP9X as a deubiquitinase of BCL9, implicating USP9X in Wnt/β-catenin signaling and breast carcinogenesis.
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Zhang, Tianyi, Fu-Ning Hsu, Xiao-Jun Xie, Xiao Li, Mengmeng Liu, Xinsheng Gao, Xun Pei, Yang Liao, Wei Du, and Jun-Yuan Ji. "Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): E7469—E7478. http://dx.doi.org/10.1073/pnas.1621048114.
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Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a Drosophila model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The Axin mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of β-catenin transcriptional activities. We demonstrate pharmacologic mitigation of these phenotypes in Axin mutants by identifying bortezomib and additional peptide boronic acids. We show that the suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on α-catenin; the rescue effect is completely abolished with the depletion of α-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of β-catenin activity through α-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.
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Chen, Kun, Pei Ying Ng, Ruiying Chen, Dorothy Hu, Shawn Berry, Roland Baron, and Francesca Gori. "Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption." Proceedings of the National Academy of Sciences 116, no. 28 (June 25, 2019): 14138–43. http://dx.doi.org/10.1073/pnas.1900881116.
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Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle’s disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence ofSfrp4is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lackingSfrp4suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found thatSfrp4is expressed during bone marrow macrophage OC differentiation and that Sfrp4 significantly suppresses the ability of early and late OC precursors to respond to Rankl-induced OC differentiation.Sfrp4deletion in OCs resulted in activation of canonical Wnt/β-catenin and noncanonical Wnt/Ror2/Jnk signaling cascades. However, while inhibition of canonical Wnt/β-catenin signaling did not alter the effect ofSfrp4on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion ofRor2exclusively in OCs (CtskCreRor2fl/fl) inSfrp4null mice significantly reversed the increased number of endosteal OCs seen in these mice and reduced their cortical thinning. Altogether, these data show autocrine and paracrine effects of Sfrp4 in regulating OCgenesis and demonstrate that the increase in endosteal OCs seen inSfrp4−/−mice is a consequence of noncanonical Wnt/Ror2/Jnk signaling activation in OCs overriding the negative effect that activation of canonical Wnt/β-catenin signaling has on OCgenesis.
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He, Lu, Hong Zhou, Zhiqing Zeng, Hailun Yao, Weiping Jiang, and Hongtao Qu. "Wnt/β‐catenin signaling cascade: A promising target for glioma therapy." Journal of Cellular Physiology 234, no. 3 (September 17, 2018): 2217–28. http://dx.doi.org/10.1002/jcp.27186.
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Kim, Yong-Mi, Hong Ma, Vivian Oehler, Enzi Jiang, Cu Nguyen, David P. Masiello, Han Liu, Yi Zhao, Jerald P. Radich, and Michael Kahn. "The Gamma Catenin/CBP Complex Maintains Survivin Transcription In β-Catenin Deficient/Depleted Cancer Cells." Blood 116, no. 21 (November 19, 2010): 1218. http://dx.doi.org/10.1182/blood.v116.21.1218.1218.
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Abstract Abstract 1218 Survivin is a member of the inhibitor of apoptosis (IAP) gene family, which plays essential roles in prevention of apoptosis, cell division, and cancer development. Aberrant expression of Survivin is associated with essentially all tumors compared to their normal tissues. A number of signaling pathways are involved in the transcriptional regulation of Survivin. Previously, we demonstrated that Survivin expression is CBP/β-catenin/TCF-dependent and that ICG-001, a specific inhibitor of binding to the N-terminus of CBP, effectively attenuates Survivin expression. Now, using NCI-H28 cells, which harbor a homozygous deletion of β-catenin, we demonstrate that Survivin transcription can similarly be mediated by nuclear γ-catenin. In this study, we confirm that γ-catenin, like β-catenin, accumulates in the nucleus and that it can increase TOPFLASH reporter activity upon Wnt3a stimulation in NCI-H28 cells. In addition, overexpression of γ-catenin increases the expression of the TCF/catenin target genes Survivin and cyclinD1. This effect can be diminished by overexpression of dominant negative TCF or transactivation domain deleted γ-catenin. We demonstrate that g-catenin by binding to TCF family members and specifically recruiting the coactivator CBP drives Survivin transcription particularly in β-catenin-deficient cells indicating that γ-catenin can participate in the canonical Wnt signaling cascade. We also examined the relative expression of γ-catenin and β-catenin in 90 cases of chronic myeloid leukemia (CML) in a published gene expression microarray data base. A statistically significant negative correlation between γ-catenin and β-catenin was found in AP/BC cases (-0.389, P = 0.006). Furthermore, in subsequent independent validation studies by qPCR in 28 CP and BC patients increased g-catenin expression predominated in BC cases and was associated with concomitantly increased Survivin expression. Gene expression was 3- and 6-fold greater in BC patients as compared to CP patients, for γ-catenin and survivin, respectively. Consistent with this observation, nuclear γ-catenin accumulation was evident in this population consistent with a potential transcriptional role. Combined treatment with imatinib mesylate (IM) and ICG-001 significantly inhibited colony formation in sorted CD34+ CML progenitors (survivin+/γ-cateninhigh/β-cateninlow) isolated from one BC and one AP patient resistant to IM. Our data indicates the potential of ICG-001 to block both the CBP/γ-catenin interaction and the CBP/β-catenin interaction and this may have clinical significance in cancers in which γ-catenin plays a significant transcriptional role. Disclosures: No relevant conflicts of interest to declare.
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Saydam, Okay, Yiping Shen, Thomas Würdinger, Ozlem Senol, Elvan Boke, Marianne F. James, Bakhos A. Tannous, et al. "Downregulated MicroRNA-200a in Meningiomas Promotes Tumor Growth by Reducing E-Cadherin and Activating the Wnt/β-Catenin Signaling Pathway." Molecular and Cellular Biology 29, no. 21 (August 24, 2009): 5923–40. http://dx.doi.org/10.1128/mcb.00332-09.
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ABSTRACT Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, are usually benign, and are frequently associated with neurofibromatosis type 2. Here, we define a typical human meningioma microRNA (miRNA) profile and characterize the effects of one downregulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Upregulation of miR-200a decreased the expression of transcription factors ZEB1 and SIP1, with consequent increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Downregulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of β-catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target β-catenin mRNA, thereby inhibiting its translation and blocking Wnt/β-catenin signaling, which is frequently involved in cancer. A direct correlation was found between the downregulation of miR-200a and the upregulation of β-catenin in human meningioma samples. Thus, miR-200a appears to act as a multifunctional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and Wnt/β-catenin signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas.
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Sun, Mengyu, Dongdong Zhou, Jingwan Wu, Jing Zhou, and Jing Xu. "Sdy-1 Executes Antitumor Activity in HepG2 and HeLa Cancer Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway." Marine Drugs 20, no. 2 (February 5, 2022): 125. http://dx.doi.org/10.3390/md20020125.
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Demethylincisterol A3 (Sdy-1), a highly degraded sterol that we previously isolated from Chinese mangrove Rhizophora mucronata endophytic Pestalotiopsis sp. HQD-6, exhibits potent antitumor activity towards a variety of cancer cells. In this study, we further verified that Sdy-1 effectively inhibited the proliferation and migration of human liver (HepG2) and cervical cancer (HeLa) cells in vitro and it can induce cell apoptosis and arrest the cell cycle in the G1-phase. Mechanistically, we demonstrated that Sdy-1 executes its function via inhibition of the Wnt/β-catenin signaling pathway. Sdy-1 may not inhibit the Wnt signaling pathway through the cascade reaction from upstream to downstream, but directly acts on β-catenin to reduce its transcription level, thereby reducing the level of β-catenin protein and further reducing the expression of downstream related proteins. The possible interaction between Sdy-1 and β-catenin protein was further confirmed by molecular docking studies. In the nude mouse xenograft model, Sdy-1 can also significantly inhibit tumor growth. These results indicated that Sdy-1 is an efficient inhibitor of the Wnt signaling pathway and is a promising antitumor candidate for therapeutic applications.
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Hseu, You-Cheng, Hsiao-Tung Tsou, K. J. Senthil Kumar, Kai-Yuan Lin, Hsueh-Wei Chang, and Hsin-Ling Yang. "The Antitumor Activity ofAntrodia camphoratain Melanoma Cells: Modulation of Wnt/β-Catenin Signaling Pathways." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/197309.
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Antrodia camphorata(AC) is well known in Taiwan as a traditional Chinese medicine. The aim of this study was to investigate whether a fermented culture broth of AC could inhibit melanoma proliferation and progressionviasuppression of the Wnt/β-catenin signaling pathway. In this study, we observed that AC treatment resulted in decreased cell viability and disturbed Wnt/β-catenin cascade in B16F10 and/or B16F1 melanoma cells. This result was accompanied by a decrease in the expression of Wnt/β-catenin transcriptional targets, including c-Myc and survivin. Furthermore, treatment of melanoma cells with AC resulted in a significant increase in apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9 and -3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. We also observed that AC caused G1phase arrest mediated by a downregulation of cyclin D1 and CDK4 and increased p21 and p27 expression. In addition, we demonstrated that non- and subcytotoxic concentrations of AC markedly inhibited migration and invasion of highly metastatic B16F10 cells. The antimetastatic effect of AC was further confirmed by reductions in the levels of MMP-2, MMP-9, and VEGF expression. These results suggest thatAntrodia camphoratamay exert antitumor activity by downregulating the Wnt/β-catenin pathways.
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Zhu, G., Y. Wang, B. Huang, J. Liang, Y. Ding, A. Xu, and W. Wu. "A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells." Oncogene 31, no. 8 (August 8, 2011): 1001–12. http://dx.doi.org/10.1038/onc.2011.294.
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Kurimoto, S., J. Jung, M. Tapadia, J. Lengfeld, D. Agalliu, M. Waterman, T. Mozaffar, and R. Gupta. "Activation of the Wnt/β-catenin signaling cascade after traumatic nerve injury." Neuroscience 294 (May 2015): 101–8. http://dx.doi.org/10.1016/j.neuroscience.2015.02.049.
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Cha, Nier, Wei Liu, Na Yang, Shengzhi Xie, Yanwei Gao, Xia Chen, Xiaoli Wang, and Jun Ren. "Oncogenicity of LHX4 in colorectal cancer through Wnt/β-catenin/TCF4 cascade." Tumor Biology 35, no. 10 (July 19, 2014): 10319–24. http://dx.doi.org/10.1007/s13277-014-2210-8.
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Singh, Rajan, Shalender Bhasin, Melissa Braga, Jorge N. Artaza, Shehla Pervin, Wayne E. Taylor, Venkatesh Krishnan, Satyesh K. Sinha, Tripathi B. Rajavashisth, and Ravi Jasuja. "Regulation of Myogenic Differentiation by Androgens: Cross Talk between Androgen Receptor/ β-Catenin and Follistatin/Transforming Growth Factor-β Signaling Pathways." Endocrinology 150, no. 3 (October 23, 2008): 1259–68. http://dx.doi.org/10.1210/en.2008-0858.
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Androgens are important regulators of body composition and promote myogenic differentiation and inhibit adipogenesis of mesenchymal, multipotent cells. Here, we investigated the mechanisms by which androgens induce myogenic differentiation of mesenchymal multipotent cells. Incubation of mesenchymal multipotent C3H 10T1/2 cells with testosterone and dihydrotestosterone promoted nuclear translocation of androgen receptor (AR)/β-catenin complex and physical interaction of AR, β-catenin, and T-cell factor-4 (TCF-4). Inhibition of β-catenin by small inhibitory RNAs significantly decreased testosterone-induced stimulation of myogenic differentiation. Overexpression of TCF-4, a molecule downstream of β-catenin in Wnt signaling cascade, in C3H 10T1/2 cells significantly up-regulated expression of myoD and myosin heavy chain II proteins and of follistatin (Fst), which binds and antagonizes native ligands of the TGF-β/Smad pathway. Gene array analysis of C3H 10T1/2 cells treated with testosterone revealed that testosterone up-regulated the expression of Fst and modified the expression of several signaling molecules involved in the TGF-β/Smad pathway, including Smad7. Lowering of testosterone levels in mice by orchidectomy led to a significant decrease in Fst and Smad7 expression; conversely, testosterone supplementation in castrated mice up-regulated Fst and Smad7 mRNA expression in androgen-responsive levator ani muscle. Testosterone-induced up-regulation of MyoD and myosin heavy chain II proteins in C3H 10T1/2 cells was abolished in cells simultaneously treated with anti-Fst antibody, suggesting an essential role of Fst during testosterone regulation of myogenic differentiation. In conclusion, our data suggest the involvement of AR, β-catenin, and TCF-4 pathway during androgen action to activate a number of Wnt target genes, including Fst, and cross communication with the Smad signaling pathway. Androgen-induced myogenic differentiation in mouse multipotent C3H 10T1/2 cells is mediated through androgen receptor/β-catenin signaling pathway to upregulate follistatin and cross-communication with TGF-β/Smad signaling pathway.
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Arroyo, Rita, Sonia López, Enrique Romo, Gonzalo Montoya, Lía Hoz, Claudia Pedraza, Yonathan Garfias, and Higinio Arzate. "Carboxy-Terminal Cementum Protein 1-Derived Peptide 4 (cemp1-p4) Promotes Mineralization through wnt/β-catenin Signaling in Human Oral Mucosa Stem Cells." International Journal of Molecular Sciences 21, no. 4 (February 15, 2020): 1307. http://dx.doi.org/10.3390/ijms21041307.
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Human cementum protein 1 (CEMP1) is known to induce cementoblast and osteoblast differentiation and alkaline phosphatase (ALP) activity in human periodontal ligament-derived cells in vitro and promotes bone regeneration in vivo. CEMP1′s secondary structure analysis shows that it has a random-coiled structure and is considered an Intrinsic Disordered Protein (IDP). CEMP1′s short peptide sequences mimic the biological capabilities of CEMP1. However, the role and mechanisms of CEMP1′s C-terminal-derived synthetic peptide (CEMP1-p4) in the canonical Wnt/β-catenin signaling pathway are yet to be described. Here we report that CEMP1-p4 promotes proliferation and differentiation of Human Oral Mucosa Stem Cells (HOMSCs) by activating the Wnt/β-catenin pathway. CEMP1-p4 stimulation upregulated the expression of β-catenin and glycogen synthase kinase 3 beta (GSK-3B) and activated the transcription factors TCF1/7 and Lymphoid Enhancer binding Factor 1 (LEF1) at the mRNA and protein levels. We found translocation of β-catenin to the nucleus in CEMP1-p4-treated cultures. The peptide also penetrates the cell membrane and aggregates around the cell nucleus. Analysis of CEMP1-p4 secondary structure revealed that it has a random-coiled structure. Its biological activities included the induction to nucleate hydroxyapatite crystals. In CEMP1-p4-treated HOMSCs, ALP activity and calcium deposits increased. Expression of Osterix (OSX), Runt-related transcription factor 2 (RUNX2), Integrin binding sialoproptein (IBSP) and osteocalcin (OCN) were upregulated. Altogether, these data show that CEMP1-p4 plays a direct role in the differentiation of HOMSCs to a “mineralizing-like” phenotype by activating the β-catenin signaling cascade.
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Caracci, Mario O., Miguel E. Ávila, and Giancarlo V. De Ferrari. "Synaptic Wnt/GSK3βSignaling Hub in Autism." Neural Plasticity 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/9603751.
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Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak andde novovariants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β(GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3βactivity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD.
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Chiarini, Francesca, Francesca Paganelli, Alberto M. Martelli, and Camilla Evangelisti. "The Role Played by Wnt/β-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia." International Journal of Molecular Sciences 21, no. 3 (February 7, 2020): 1098. http://dx.doi.org/10.3390/ijms21031098.
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Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/β-catenin in hematopoietic malignancies and provides information on the current status of Wnt/β-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.
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Irrera, Natasha, Alessandra Bitto, Mario Vaccaro, Federica Mannino, Violetta Squadrito, Giovanni Pallio, Vincenzo Arcoraci, et al. "PDRN, a Bioactive Natural Compound, Ameliorates Imiquimod-Induced Psoriasis through NF-κB Pathway Inhibition and Wnt/β-Catenin Signaling Modulation." International Journal of Molecular Sciences 21, no. 4 (February 12, 2020): 1215. http://dx.doi.org/10.3390/ijms21041215.
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Nuclear factor-κB (NF-κB) plays a central role in psoriasis and canonical Wnt/β-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation blocks NF-κB and boosts the Wnt/β-catenin signaling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Psoriasis-like lesions were induced by a daily application of imiquimod (IMQ) on the shaved back skin of mice for 7 days. Animals were randomly assigned to the following groups: Sham psoriasis challenged with Vaseline; IMQ animals challenged with imiquimod; and IMQ animals treated with PDRN (8 mg/kg/ip). An additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. PDRN restored a normal skin architecture, whereas istradefylline abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pro-inflammatory cytokines, prompted Wnt signaling, reduced IL-2 and increased IL-10. PDRN also reverted the LPS repressed Wnt-1/β-catenin in human keratinocytes and these effects were abolished by ZM241385, an A2A receptor antagonist. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis. PDRN anti-psoriasis potential may be linked to a “dual mode” of action: NF-κB inhibition and Wnt/β-catenin stimulation.
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Stewart, Melanie K., Pascal Bernard, Ching-Seng Ang, Deidre M. Mattiske, and Andrew J. Pask. "Oestrogen Activates the MAP3K1 Cascade and β-Catenin to Promote Granulosa-like Cell Fate in a Human Testis-Derived Cell Line." International Journal of Molecular Sciences 22, no. 18 (September 17, 2021): 10046. http://dx.doi.org/10.3390/ijms221810046.
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Sex determination triggers the differentiation of the bi-potential gonad into either an ovary or testis. In non-mammalian vertebrates, the presence or absence of oestrogen dictates gonad differentiation, while in mammals, this mechanism has been supplanted by the testis-determining gene SRY. Exogenous oestrogen can override this genetic trigger to shift somatic cell fate in the gonad towards ovarian developmental pathways by limiting the bioavailability of the key testis factor SOX9 within somatic cells. Our previous work has implicated the MAPK pathway in mediating the rapid cellular response to oestrogen. We performed proteomic and phosphoproteomic analyses to investigate the precise mechanism through which oestrogen impacts these pathways to activate β-catenin—a factor essential for ovarian development. We show that oestrogen can activate β-catenin within 30 min, concomitant with the cytoplasmic retention of SOX9. This occurs through changes to the MAP3K1 cascade, suggesting this pathway is a mechanism through which oestrogen influences gonad somatic cell fate. We demonstrate that oestrogen can promote the shift from SOX9 pro-testis activity to β-catenin pro-ovary activity through activation of MAP3K1. Our findings define a previously unknown mechanism through which oestrogen can promote a switch in gonad somatic cell fate and provided novel insights into the impacts of exogenous oestrogen exposure on the testis.
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Xie, Lulu, Minjing Li, Desheng Liu, Xia Wang, Peiyuan Wang, Hanhan Dai, Wei Yang, Wei Liu, Xuemei Hu, and Mingdong Zhao. "Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/β-catenin Signaling Pathway." Molecules 24, no. 3 (January 22, 2019): 393. http://dx.doi.org/10.3390/molecules24030393.
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Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/β-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/β-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/β-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/β-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.
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Gradl, Dietmar, Michael Kühl, and Doris Wedlich. "The Wnt/Wg Signal Transducer β-Catenin Controls Fibronectin Expression." Molecular and Cellular Biology 19, no. 8 (August 1, 1999): 5576–87. http://dx.doi.org/10.1128/mcb.19.8.5576.
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ABSTRACT β-Catenin stabilizes the cadherin cell adhesion complex but, as a component of the Wnt/Wg signaling pathway, also controls gene expression by forming a heterodimer with a transcription factor of the LEF-TCF family. We demonstrate that the substrate adhesion molecule fibronectin is a direct target of Wnt/Wg signaling. Nuclear depletion of β-catenin following cadherin transfection in Xenopusfibroblasts resulted in downregulation of fibronectin expression which was restored by activating the Wnt/Wg signaling cascade via LiCl treatment or transfection of either Xwnt-8 or β-catenin. We isolated the Xenopus fibronectin gene (FN) promoter and found four putative LEF-TCF binding sites. By comparing the activities of different fibronectin gene reporter constructs in fibroblasts and cadherin transfectants, the LEF-TCF site at position −368 was identified as a Wnt/Wg response element. LEF-1-related proteins were found in nuclei of the fibroblasts but were absent in a kidney epithelial cell line. Consistent with the lack of these transcription factors, the FN promoter was silent in the epithelial cells but was activated upon transfection of LEF-1. Wild-typeXenopus Tcf-3 (XTcf-3) was unable to activateFN promoter reporter constructs, while a mutant lacking the groucho binding region behaved like LEF-1. In contrast to XTcf-3, LEF-1 does not interact with groucho proteins, which turn TCFs into activators or repressors (J. Roose, M. Molenaar, J. Hurenkamp, J. Peterson, H. Brantjes, P. Moerer, M. van de Wetering, O. Destreé, and H. Clevers, Nature 395:608–612, 1998). Together these data provide evidence that expressing LEF-1 enables fibroblasts, in contrast to epithelial cells, to respond to the Wnt/Wg signal via β-catenin in stimulating fibronectin gene transcription. Our findings further promote the idea that due to its dual function, β-catenin regulates the balance between cell-cell and cell-substrate adhesion.
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Pérez-Palma, Eduardo, Víctor Andrade, Mario O. Caracci, Bernabé I. Bustos, Camilo Villaman, Matías A. Medina, Miguel E. Ávila, Giorgia D. Ugarte, and Giancarlo V. De Ferrari. "Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons." Neural Plasticity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/4672841.
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Wnt/β-catenin signaling modulates brain development and function and its deregulation underlies pathological changes occurring in neurodegenerative and neurodevelopmental disorders. Since one of the main effects of Wnt/β-catenin signaling is the modulation of target genes, in the present work we examined global transcriptional changes induced by short-term Wnt3a treatment (4 h) in primary cultures of rat hippocampal neurons. RNAseq experiments allowed the identification of 170 differentially expressed genes, including known Wnt/β-catenin target genes such as Notum, Axin2, and Lef1, as well as novel potential candidates Fam84a, Stk32a, and Itga9. Main biological processes enriched with differentially expressed genes included neural precursor (GO:0061364,p-adjusted = 2.5 × 10−7), forebrain development (GO:0030900,p-adjusted = 7.3 × 10−7), and stem cell differentiation (GO:0048863p-adjusted = 7.3 × 10−7). Likewise, following activation of the signaling cascade, the expression of a significant number of genes with transcription factor activity (GO:0043565,p-adjusted = 4.1 × 10−6) was induced. We also studied molecular networks enriched upon Wnt3a activation and detected three highly significant expression modules involved in glycerolipid metabolic process (GO:0046486,p-adjusted = 4.5 × 10−19), learning or memory (GO:0007611,p-adjusted = 4.0 × 10−5), and neurotransmitter secretion (GO:0007269,p-adjusted = 5.3 × 10−12). Our results indicate that Wnt/β-catenin mediated transcription controls multiple biological processes related to neuronal structure and activity that are affected in synaptic dysfunction disorders.