• International Journal of Oral Biology
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• v.34 no.2
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• pp.53-59
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• 2009

Periodontal ligament (PDL) tissue is a connective tissue that is interposed between the roots of the teeth and the inner wall of the alveolar bone socket. PDL is always exposed to physiologic mechanical force such as masticatory force and PDL cells play important roles during orthodontic tooth movement by synthesizing and secreting different mediators involved in bone remodeling. The Wnt/${\beta}$-catenin signaling pathway was recently shown to play a significant role in the control of bone formation. In the present study, we applied cyclic tensile stress of 20% elongation to cultured human PDL cells and assessed its impact after six days upon components of the Wnt/${\beta}$-catenin signaling pathway. RTPCR analysis showed that Wnt1a, Wnt3a, Wnt10b and the Wnt receptor LRP5 were down-regulated, whereas the Wnt inhibitor DKK1 was up-regulated in response to these stress conditions. In contrast, little change was detected in the mRNA expression of Wnt5a, Wnt7b, Fz1, and LRP6. By western blotting we found decreased expression of the ${\beta}$-catenin and p-GSK-3${\beta}$ proteins. Our results thus show that mechanical stress suppresses the canonical Wnt/${\beta}$-catenin signaling pathway in PDL cells.

• Proceedings of the KSAR Conference
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• 2002.06a
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• pp.82-82
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• 2002

The Wnt signaling pathway plays pivotal roles in embryonic development and oncogenesis through various signaling molecules inculding Frizzled receptor, recently characterized LRP5/6 and Dickkopf protein. Although Wnt signaling has been characterized in both developmental and oncogenic processes, little is known about its function in the normal adult. The ability of LRP5 to bind apolipoprotein E(apoE) and the abundant expression of LRP5 transcripts in hepatocytes, raise the possibility that LRP5 plays a role in the hepatic clearance of ApoE-containing chylomicron remonants, a major plasma lipoprotein carrying diet-derived cholesterol. (omitted)

• Journal of Life Science
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• v.28 no.9
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• pp.1016-1021
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• 2018

Clostridium difficile toxin A causes pseudomembranous colitis. The pathogenesis of toxin A-induced colonic inflammation includes toxin A-dependent epithelial cell apoptosis, resulting in the loss of barrier function provided by epithelial cells against luminal pathogens. Toxin A-dependent epithelial cell apoptosis has been linked to toxin A-induced production of reaction oxygen species and subsequent p38MAPK activation; $p21^{CIP1/WAF1}$ upregulation-dependent cell cycle arrest; cytoskeletal disaggregation; and/or the induction of Fas ligand on epithelial cells. However, the molecular mechanisms underlying toxin A-induced apoptosis remain poorly understood. This study tested whether toxin A could block the Wnt signaling pathway, which is involved in gut epithelial cell proliferation, differentiation and antiapoptotic progression. Toxin A treatment of nontransformed human colonocytes (NCM460) rapidly reduced ${\beta}$-catenin protein, an essential component of the Wnt signaling pathway. Exposure of mouse ileum to toxin A also significantly reduced ${\beta}$-catenin protein levels. MG132 inhibition of proteasome-dependent protein degradation resulted in the recovery of toxin A-mediated reduction of ${\beta}$-catenin, indicating that toxin A may activate intracellular processes, such as $GSK3{\beta}$, to promote degradation of ${\beta}$-catenin. Immunoblot analysis showed that toxin A increased active phosphorylation of $GSK3{\beta}$. Because the Wnt signaling pathway is essential for gut epithelial cell proliferation and anti-apoptotic processes, our results suggest that toxin A-mediated inhibition of the Wnt signaling pathway may be required for maximal toxin A-induced apoptosis of gut epithelial cells.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2001.11a
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• pp.108-108
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• 2001

Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of ${\beta}$-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6 kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved non-coding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by ${\beta}$-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility-shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6 kb genomic sequence was sufficient to direct the tissue specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2. Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.

• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.465-472
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• 2020

Colorectal cancer (CRC) is one of the most malignant type of cancers and its incidence is steadily increasing, due to life style factors that include western diet. Abnormal activation of canonical Wnt/β-catenin signaling pathway plays an important role in colorectal carcinogenesis. Therefore, targeting Wnt/β-catenin signaling has been considered a crucial strategy in the discovery of small molecules for CRC. In the present study, we found that Nodosin, an ent-kaurene diterpenoid isolated from Isodon serra, effectively inhibits the proliferation of human colon cancer HCT116 cells. Mechanistically, Nodosin effectively inhibited the overactivated transcriptional activity of β-catenin/T-cell factor (TCF) determined by Wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. The expression of Wnt/β-catenin target genes such as Axin2, cyclin D1, and survivin were also suppressed by Nodosin in HCT116 cells. Further study revealed that a longer exposure of Nodosin induced the G₂/M phase cell cycle arrest and subsequently apoptosis in HCT116 cells. These findings suggest that the anti-proliferative activity of Nodosin in colorectal cancer cells might in part be associated with the regulation of Wnt/β-catenin signaling pathway.

• Development and Reproduction
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• v.11 no.3
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• pp.141-153
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• 2007

The Wnt signaling pathway regulates cell proliferation and differentiation during development of multicellular organisms and plays pivotal roles in the maintenance of homeostasis in adult tissues. Therefore misregulation of Wnt signaling could be a pathogenesis of diverse human diseases such as cancers. Recently, the list of diseases that may be linked to the misregulation of Wnt signaling has exploded and more people are getting interested in the way of controlling Wnt signaling. There are a lot of review papers, however, since most of them have focused on specific issues for experts in Wnt signaling it may be difficult for new comers to understand the overall background and current status of Wnt signaling. In this review, we present data and interpretations for the overall processes of Wnt signal transduction to understand the past and current status of Wnt signaling.

• BMB Reports
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• v.49 no.8
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• pp.403-404
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• 2016

The Wnt/β-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in embryonic development and adult homeostasis. However, we have limited information about the involvement of Wnt/β-catenin signaling in the lymphatic vascular system that regulates fluid homeostasis by absorbing interstitial fluid and returning it to blood circulation. In this recent publication we report that canonical Wnt/β-catenin signaling is highly active and critical for the formation of lymphovenus valves (LVVs) and lymphatic valves (LVs). β-catenin directly associates with the regulatory elements of the lymphedema-associated transcription factor, FOXC2 and activates its expression in an oscillatory shear stress (OSS)-dependent manner. The phenotype of β-catenin null embryos was rescued by FOXC2 overexpression. These results suggest that Wnt/β-catenin signaling is a mechanotransducer that links fluid force with lymphatic vascular development.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1075-1079
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• 2014

MicroRNA expression is a research focus in studies of tumors. This article concentrates attention on potential links between tumors caused by mouse mammary tumor virus (MMTV) and human breast cancer, in order to provide theoretical basis for using mouse model to search for miRNA effects mediated by Wnt/beta-catenin signaling in human breast cancer. By analyzing interactions between miRNAs and the Wnt/beta-catenin signaling pathway in breast cancer, we hope to casts light on more biological functions of miRNAs in the process of tumor formation and growth and to explore their potential value in cancer diagnosis, prognosis and treatment. Our endeavor aimed at providing theoretical basis for finding safer, more effective methods for treatment of human breast cancer at the miRNA molecular level.

• BMB Reports
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• v.51 no.9
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• pp.425-426
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• 2018

As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to ${\beta}-catenin$ in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, ${\alpha}-catenin$, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion.

• BMB Reports
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• v.47 no.12
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• pp.666-672
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• 2014

The Wnt signaling pathway is well known to play major roles in skeletal development and homeostasis. In certain aspects, fracture repair mimics the process of bone embryonic development. Thus, the importance of Wnt signaling in fracture healing has become more apparent in recent years. Here, we summarize recent research progress in the area, which may be conducive to the development of Wnt-based therapeutic strategies for bone repair.