共查询到20条相似文献,搜索用时 0 毫秒
1.
The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis, which is regulated by multiple signaling pathways. The Wnt/β-catenin pathway has a critical role in this process. Previously, we have shown that the calcineurin-dependent nuclear factor of activated T cell (NFAT) is involved in the regulation of intestinal cell differentiation, as noted by the alteration of brush-border enzyme intestinal alkaline phosphatase (IAP) activity. Here, we show that calcineurin-independent NFAT5 interacts with β-catenin to repress Wnt signaling. We found that overexpression of NFAT5 inhibits, whereas knockdown of NFAT5 increases, TOPflash reporter activity and the expression of Wnt/β-catenin target genes, suggesting that NFAT5 inhibits Wnt signaling. In addition, we demonstrated that NFAT5 directly interacts with the C-terminal transactivation domain (TAD) of β-catenin, inhibits CBP interaction with β-catenin, and inhibits CBP-mediated β-catenin acetylation. Moreover, NFAT5 is expressed in the mucosa of human intestine, with the most pronounced staining in the most differentiated region near the epithelial surface. Knockdown of NFAT5 attenuated sodium butyrate (NaBT)-mediated induction of IAP and sucrase activities; overexpression of NFAT5 induced IAP promoter activity. In summary, we provide evidence showing that NFAT5 is a regulator of Wnt signaling. Importantly, our results suggest that NFAT5 regulation of intestinal cell differentiation may be through inhibition of Wnt/β-catenin signaling. 相似文献
2.
3.
Van Raay TJ Fortino NJ Miller BW Ma H Lau G Li C Franklin JL Attisano L Solnica-Krezel L Coffey RJ 《PloS one》2011,6(4):e18650
Cyto-nuclear shuttling of β-catenin is at the epicenter of the canonical Wnt pathway and mutations in genes that result in excessive nuclear accumulation of β-catenin are the driving force behind the initiation of many cancers. Recently, Naked Cuticle homolog 1 (Nkd1) has been identified as a Wnt-induced intracellular negative regulator of canonical Wnt signaling. The current model suggests that Nkd1 acts between Disheveled (Dvl) and β-catenin. Here, we employ the zebrafish embryo to characterize the cellular and biochemical role of Nkd1 in vivo. We demonstrate that Nkd1 binds to β-catenin and prevents its nuclear accumulation. We also show that this interaction is conserved in mammalian cultured cells. Further, we demonstrate that Nkd1 function is dependent on its interaction with the cell membrane. Given the conserved nature of Nkd1, our results shed light on the negative feedback regulation of Wnt signaling through the Nkd1-mediated negative control of nuclear accumulation of β-catenin. 相似文献
4.
5.
6.
K. V. Kulikova A. V. Posvyatenko N. V. Gnuchev G. P. Georgiev A. V. Kibardin S. S. Larin 《Molecular Biology》2011,45(5):816-822
In most cases, advanced stages of melanoma are practically incurable due to high metastatic potential of tumor cells. Multiple
observations support the idea that aberrations in the Wnt signaling pathway play a significant role in melanoma development
and progression. Canonical Wnt signaling activation results in stabilization and accumulation of the major effector molecule
called & gb-catenin. Mutations promoting & gb-catenin stabilization and, thereby, activation of canonical Wnt signaling pathway
are frequently found in different cancers but rarely observed in melanomas. Nevertheless, & gb-catenin nuclear and cytoplasmic
accumulation is the feature of many human melanoma cell lines and original tumors. That is why the aim of the investigation
was to elucidate the relation between & gb-catenin intracellular localization and activity status of Wnt signaling pathway
in human melanoma cell lines. Ten human melanoma cell lines were characterized on the basis of the following parameters: canonical
Wnt ligand expression, intracellular & gb-catenin localization and activity status of canonical Wnt signaling pathway. Here,
it has been demonstrated that nuclear localization of & gb-catenin does not always correspond to active status of canonical
Wnt signaling pathway. Moreover, in the majority of cell lines with nuclear & gb-catenin, canonical Wnt signaling cannot be
activated by exogenous expression of an appropriate ligand. Human melanoma cell lines differ in activity of canonical Wnt
signaling pathway as well as in mechanisms of its regulation. Therefore, pathway-targeted potential antineoplastic therapy
requires the formation of a & ldmolecular pattern of cancer” for localization of the defect in Wnt signaling cascade in each
case. 相似文献
7.
8.
9.
10.
11.
12.
13.
14.
Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl4-induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. 相似文献
15.
The activation of developmental signaling pathways such as Notch, Hedgehog and Wnt has implications in the onset and progression of numerous types of cancer. Consequently, targeting of such pathways is considered an attractive therapeutic approach. Inhibition of the Wnt signaling cascade proves to be complicated, in part, due to the lack of druggable pathway components. The central hub in Wnt signaling is the protein β-catenin, which is involved in numerous protein–protein interactions. In general, the inhibition of protein–protein interactions is challenging in particular with binding interfaces lacking pronounced hydrophobic pockets. Herein, we give an overview of β-catenin–protein interactions, and we review active agents that were reported to inhibit canonical Wnt signaling via direct targeting of β-catenin. 相似文献
16.
17.
18.
《Cell Adhesion & Migration》2013,7(3):431-438
In neural crest cell development, the expression of the cell adhesion proteins cadherin-7 and cadherin-11 commences after delamination of the neural crest cells from the neuroepithelium. The canonical Wnt signaling pathway is known to drive this delamination step and is a candidate for inducing expression of these cadherins at this time. This project was initiated to investigate the role of canonical Wnt signaling in the expression of cadherin-7 and cadherin-11 by treating neural crest cells with Wnt3a ligand. Expression of cadherin-11 was first confirmed in the neural crest cells for the chicken embryo. The changes in the expression level of cadherin-7 and -11 following the treatment with Wnt3a ligand were studied using real-time RT-PCR and immunostaining. Statistically significant up-regulation in the mRNA expression of cadherin-7 and cadherin-11 and in the amount of cadherin-7 and cadherin-11 protein found in cell-cell interfaces between neural crest cells was observed in response to Wnt, demonstrating that cadherin-7 and cadherin-11 expressed by the migrating neural crest cells can be regulated by the canonical Wnt pathway. 相似文献
19.