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Ubiquitin Ligase RNF146 Regulates Tankyrase and Axin to Promote Wnt Signaling  [PDF]
Marinella G. Callow,Hoanh Tran,Lilian Phu,Ted Lau,James Lee,Wendy N. Sandoval,Peter S. Liu,Sheila Bheddah,Janet Tao,Jennie R. Lill,Jo-Anne Hongo,David Davis,Donald S. Kirkpatrick,Paul Polakis,Mike Costa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022595
Abstract: Canonical Wnt signaling is controlled intracellularly by the level of β-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates β-catenin to target it for ubiquitylation and proteasomal degradation. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degradation of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling.
Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma  [PDF]
Tian Yang, Sheng-Yun Cai, Jin Zhang, Jun-Hua Lu, Chuan Lin, Jian Zhai, Meng-Chao Wu, Feng Shen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039668
Abstract: Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8.
Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer  [PDF]
María Jesús Larriba, Paloma Ordó?ez-Morán, Irene Chicote, Génesis Martín-Fernández, Isabel Puig, Alberto Mu?oz, Héctor G. Pálmer
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023524
Abstract: Aberrant activation of the Wnt/β-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear β-catenin and the induction of its target genes. Apcmin/+ mice are the most commonly used model for colon cancer. They harbor a mutated Apc allele and develop intestinal adenomas and carcinomas during the first months of life. This phenotype is caused by the mutation of the second Apc allele and the consequent accumulation of nuclear β-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear β-catenin levels in colon cancer in vivo. By appropriate breeding of Apcmin/+ mice and Vdr+/? mice we have generated animals expressing a mutated Apc allele and two, one, or none Vdr wild type alleles. Lack of Vdr increased the number of colonic Aberrant Crypt Foci (ACF) but not that of adenomas or carcinomas in either small intestine or colon. Importantly, colon ACF and tumors of Apcmin/+Vdr-/- mice had increased nuclear β-catenin and the tumors reached a larger size than those of Apcmin/+Vdr+/+. Both ACF and carcinomas in Apcmin/+Vdr-/- mice showed higher expression of β-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced β-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)2D3 to promote the relocation of β-catenin from the nucleus to the plasma membrane and to inhibit β-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear β-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/β-catenin pathway.
miRNA-21过表达对乳鼠星形胶质细胞凋亡及Wnt/β-catenin信号通路相关蛋白表达的影响
Effects of miRNA-21 overexpression on apoptosis and expressions of Wnt/β-catenin signaling pathway related proteins in astrocytes from neonate rats
 [PDF]

朱睿明,邢方岚,张起顺,,
- , 2018, DOI: 10.13705/j.issn.1671-6825.2018.07.006
Abstract: 目的:探讨miRNA-21(miR-21)过表达对乳鼠星形胶质细胞(AS)凋亡及Wnt/β-catenin信号通路相关蛋白表达的影响。方法:AS分为3组,空白对照组、H2O2组(400 μmol/L的H2O2处理AS 24 h)和miR-21+H2O2组(miR-21 mimics转染AS 24 h后用400 μmol/L的H2O2处理细胞24 h)。采用qRT-PCR检测3组细胞miR-21的表达,流式细胞术检测细胞凋亡,Western blot检测β-catenin、c-myc和Bax蛋白的表达。结果:与空白对照组比较,H2O2组miR-21表达降低,细胞凋亡率升高,β-catenin和c-myc表达降低,Bax表达升高(P<0.05); 与H2O2组比较,miR-21+H2O2组miR-21表达升高,细胞凋亡率降低,β-catenin和c-myc蛋白表达升高,Bax蛋白表达降低(P<0.05)。结论:过表达miR-21可降低AS凋亡,其机制可能与Wnt/β-catenin信号通路的激活有关。
Aim:To investigate the effect of miRNA-21(miR-21)gene overexpression on the apoptosis of astrocytes and the expressions of Wnt/β-catenin signaling pathway-related proteins.Methods:Astrocytes were divided into 3 groups,namely, blank control group, H2O2 group and miR-21+H2O2 group. qRT-PCR was used to detect the expression of miR-21 mRNA,flow cytometry was used to detect cell apoptosis,and Western blot was used to detect the expressions of β-catenin, c-myc and Bax protein.Results:Compared with blank control group,the expression of miR-21 in the H2O2 group decreased, the apoptosis rate increased, the expressions of β-catenin and c-myc decreased, and the expression of Bax increased(P<0.05); compared with the H2O2 group, the miR-21 expression in the miR-21+H2O2 group increased, the apoptosis rate decreased, the expressions of β-catenin and c-myc increased, and the expression of Bax decreased(P<0.05).Conclusion:Overexpression of miR-21 could reduce the apoptosis of astrocytes, which may be related to the activation of Wnt/β-catenin signaling pathway
Wnt/β-Catenin Signaling Enhances Cyclooxygenase-2 (COX2) Transcriptional Activity in Gastric Cancer Cells  [PDF]
Felipe Nu?ez,Soraya Bravo,Fernando Cruzat,Martín Montecino,Giancarlo V. De Ferrari
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018562
Abstract: Increased expression of the cyclooxygenase-2 enzyme (COX2) is one of the main characteristics of gastric cancer (GC), which is a leading cause of death in the world, particularly in Asia and South America. Although the Wnt/β-catenin signaling pathway has been involved in the transcriptional activation of the COX2 gene, the precise mechanism modulating this response is still unknown.
Oncogenic Function of DACT1 in Colon Cancer through the Regulation of β-catenin  [PDF]
Guohong Yuan, Chongkai Wang, Chaolai Ma, Ning Chen, Qinghe Tian, Tonglin Zhang, Wei Fu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034004
Abstract: The Wnt/β-catenin signaling pathway plays important roles in the progression of colon cancer. DACT1 has been identified as a modulator of Wnt signaling through its interaction with Dishevelled (Dvl), a central mediator of both the canonical and noncanonical Wnt pathways. However, the functions of DACT1 in the WNT/β-catenin signaling pathway remain unclear. Here, we present evidence that DACT1 is an important positive regulator in colon cancer through regulating the stability and sublocation of β-catenin. We have shown that DACT1 promotes cancer cell proliferation in vitro and tumor growth in vivo and enhances the migratory and invasive potential of colon cancer cells. Furthermore, the higher expression of DACT1 not only increases the nuclear and cytoplasmic fractions of β-catenin, but also increases its membrane-associated fraction. The overexpression of DACT1 leads to the increased accumulation of nonphosphorylated β-catenin in the cytoplasm and particularly in the nuclei. We have demonstrated that DACT1 interacts with GSK-3β and β-catenin. DACT1 stabilizes β-catenin via DACT1-induced effects on GSK-3β and directly interacts with β-catenin proteins. The level of phosphorylated GSK-3β at Ser9 is significantly increased following the elevated expression of DACT1. DACT1 mediates the subcellular localization of β-catenin via increasing the level of phosphorylated GSK-3β at Ser9 to inhibit the activity of GSK-3β. Taken together, our study identifies DACT1 as an important positive regulator in colon cancer and suggests a potential strategy for the therapeutic control of the β-catenin-dependent pathway.
MENA Is a Transcriptional Target of the Wnt/Beta-Catenin Pathway  [PDF]
Ayaz Najafov, Tuncay ?eker, ?pek Even, Gerta Hoxhaj, Osman Selvi, Duygu Esen ?zel, Ahmet Koman, Necla Birgül-?yison
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037013
Abstract: Wnt/β-catenin signalling pathway plays important roles in embryonic development and carcinogenesis. Overactivation of the pathway is one of the most common driving forces in major cancers such as colorectal and breast cancers. The downstream effectors of the pathway and its regulation of carcinogenesis and metastasis are still not very well understood. In this study, which was based on two genome-wide transcriptomics screens, we identify MENA (ENAH, Mammalian enabled homologue) as a novel transcriptional target of the Wnt/β-catenin signalling pathway. We show that the expression of MENA is upregulated upon overexpression of degradation-resistant β-catenin. Promoters of all mammalian MENA homologues contain putative binding sites for Tcf4 transcription factor – the primary effector of the Wnt/β-catenin pathway and we demonstrate functionality of these Tcf4-binding sites using luciferase reporter assays and overexpression of β-catenin, Tcf4 and dominant-negative Tcf4. In addition, lithium chloride-mediated inhibition of GSK3β also resulted in increase in MENA mRNA levels. Chromatin immunoprecipitation showed direct interaction between β-catenin and MENA promoter in Huh7 and HEK293 cells and also in mouse brain and liver tissues. Moreover, overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. Additionally, knock-down of MENA ortholog in D. melanogaster eyeful and sensitized eye cancer fly models resulted in increased tumor and metastasis formations. In summary, our study identifies MENA as novel nexus for the Wnt/β-catenin and the Notch signalling cascades.
Wnt/β-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia  [cached]
Corrêa Stephany,Binato Renata,Du Rocher Bárbara,Castelo-Branco Morgana TL
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-303
Abstract: Background The advanced phases of chronic myeloid leukemia (CML) are known to be more resistant to therapy. This resistance has been associated with the overexpression of ABCB1, which gives rise to the multidrug resistance (MDR) phenomenon. MDR is characterized by resistance to nonrelated drugs, and P-glycoprotein (encoded by ABCB1) has been implicated as the major cause of its emergence. Wnt signaling has been demonstrated to be important in several aspects of CML. Recently, Wnt signaling was linked to ABCB1 regulation through its canonical pathway, which is mediated by β-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/β-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several β-catenin binding sites. β-catenin is the mediator of canonical Wnt signaling, which is important for CML progression. Methods In this work we used the K562 cell line and its derived MDR-resistant cell line Lucena (K562/VCR) as CML study models. Real time PCR (RT-qPCR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), flow cytometry (FACS), western blot, immunofluorescence, RNA knockdown (siRNA) and Luciferase reporter approaches were used. Results β-catenin was present in the protein complex on the basal promoter of ABCB1 in both cell lines in vitro, but its binding was more pronounced in the resistant cell line in vivo. Lucena cells also exhibited higher β-catenin levels compared to its parental cell line. Wnt1 and β-catenin depletion and overexpression of nuclear β-catenin, together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling. Conclusions These results suggest, for the first time, that the Wnt/β-catenin pathway regulates ABCB1 in CML.
Examination of effects of GSK3β phosphorylation, β-catenin phosphorylation, and β-catenin degradation on kinetics of Wnt signaling pathway using computational method
Ying-Chieh Sun
Theoretical Biology and Medical Modelling , 2009, DOI: 10.1186/1742-4682-6-13
Abstract: The well-known computational Lee-Heinrich kinetic model of the wnt pathway was modified to include these effects. The rate laws of reactions in the modified model were solved numerically to examine these effects on β-catenin level.The computations showed that the β-catenin level is almost linearly proportional to the phosphorylation activity of GSK3β. The dependence of β-catenin level on the phosphorylation and degradation of free β-catenin and downstream TCF activity can be analyzed with an approximate, simple function of kinetic parameters for added reaction steps associated with effects examined, rationalizing the experimental results.The phosphorylations of β-catenin by kinases other than GSK3β involve free unphorphorylated β-catenin rather than GSK3β-phosphorylated β-catenin*. In order to account for the observed enhancement of TCF activity, the β-catenin dephosphorylation step is essential, and the kinetic parameters of β-catenin phosphorylation and degradation need to meet a condition described in the main text. These findings should be useful for future experiments.The Wnt/β-catenin signaling pathway (named wnt pathway hereafter for simplicity) plays a significant role in cell proliferation, differentiation, and apoptosis. These have implications for aspects of cell development, stem cells and cancer [1]. Many characteristics of this pathway and its role in cell signaling have been revealed in experimental studies (for review, see for example [1], and references therein and the literature listed at http://www.stanford.edu/~rnusse/wntwindow.html webcite). Briefly, wnt signaling enhances the level of the output signal protein, unphosphorylated β-catenin, which then binds with TCF to induce associated gene expression in the nucleus. At steady state (SS), the level of β-catenin is balanced by its synthesis and degradation. The so-called destruction cycle is a major mechanism of degradation, in which phosphorylation of β-catenin by GSK3b is a key step [2]. When t
The function of BCL9 in Wnt/β-catenin signaling and colorectal cancer cells
Marc de la Roche, Jesper Worm, Mariann Bienz
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-199
Abstract: We have used overexpression of dominant-negative forms of BCL9, and RNAi-mediated depletion, to study its function in human cell lines with elevated Wnt pathway activity, including colorectal cancer cells.We found that BCL9 is required for efficient β-catenin-mediated transcription in Wnt-stimulated HEK 293 cells, and in the SW480 colorectal cancer cell line whose Wnt pathway is active due to APC mutation. Dominant-negative mutants of BCL9 indicated that its function depends not only on its β-catenin ligand, but also on an unknown ligand of its C-terminus. Finally, we show that BCL9 and B9L are both Wnt-inducible genes, hyperexpressed in colorectal cancer cell lines, indicating that they are part of a positive feedback loop.BCL9 is required for efficient β-catenin-mediated transcription in human cell lines whose Wnt pathway is active, including colorectal cancer cells, indicating its potential as a drug target in colorectal cancer.The canonical Wnt signaling pathway changes the transcriptional program of cells, and controls genes with important functions during normal and malignant development [1-3]. A key effector of this pathway is β-catenin, which is normally phosphorylated and targeted for degradation by the Axin complex that also contains the Adenomatous polyposis coli (APC) tumor suppressor. This complex is inhibited in response to Wnt stimulation, allowing unphosphorylated β-catenin to accumulate and bind to the nuclear TCF/LEF factors to stimulate the transcription of Wnt target genes. This trans-activation function of β-catenin involves the recruitment of a range of different co-factors that bind to its C-terminus, including chromatin modifying and remodelling factors such as CBP, Brg-1 and SET1 [4-10], TATA-binding protein and associated factors [11,12], and also a transcriptional elongation factor [13]. Well-established transcriptional target genes of this pathway include c-myc, AXIN2 and CD44, whose expression is upregulated in a TCF-dependent fashion in
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