scholarly journals SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes

2004 ◽  
Vol 166 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Philippe Blache ◽  
Marc van de Wetering ◽  
Isabelle Duluc ◽  
Claire Domon ◽  
Philippe Berta ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intestinal Epithelium ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
High Mobility ◽  
Cell Phenotype ◽  
Expression Screening ◽  
Sox Proteins

TCF and SOX proteins belong to the high mobility group box transcription factor family. Whereas TCFs, the transcriptional effectors of the Wnt pathway, have been widely implicated in the development, homeostasis and disease of the intestine epithelium, little is known about the function of the SOX proteins in this tissue. Here, we identified SOX9 in a SOX expression screening in the mouse fetal intestine. We report that the SOX9 protein is expressed in the intestinal epithelium in a pattern characteristic of Wnt targets. We provide in vitro and in vivo evidence that a bipartite β-catenin/TCF4 transcription factor, the effector of the Wnt signaling pathway, is required for SOX9 expression in epithelial cells. Finally, in colon epithelium-derived cells, SOX9 transcriptionally represses the CDX2 and MUC2 genes, normally expressed in the mature villus cells of the intestinal epithelium, and may therefore contribute to the Wnt-dependent maintenance of a progenitor cell phenotype.

scholarly journals The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

2012 ◽  
Vol 303 (9) ◽  
pp. E1166-E1176 ◽  
Author(s):  
Wilfred Ip ◽  
Weijuan Shao ◽  
Yu-ting Alex Chiang ◽  
Tianru Jin
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Hepatic Gluconeogenesis

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.

scholarly journals Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling Pathway

2001 ◽  
Vol 75 (6) ◽  
pp. 2857-2865 ◽  
Author(s):  
Michele Brunori ◽  
Maddalena Malerba ◽  
Haruhiko Kashiwazaki ◽  
Richard Iggo
Keyword(s):  
Wnt Signaling ◽  
Cancer Cells ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Lung Model ◽  
Colorectal Tumors ◽  
Colon Tumors ◽  
Treat All

ABSTRACT Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncogenic defects. Selectively replicating viruses have a major advantage over nonreplicating viruses to target these defects because the therapeutic effect of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating adenoviruses that express the viral E1B and E2 genes from promoters controlled by the Tcf4 transcription factor. Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and β-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but not all, cell lines with activation of the wnt pathway. Viruses with Tcf regulation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells and WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable β-catenin mutant into normal fibroblasts renders the cells permissive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces the inflammatory response in a rodent lung model in vivo. Replicating adenoviruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but additional changes will be required to produce a virus that can be used to treat all colon tumors.

scholarly journals RAB11A mediates the proliferation and motility of esophageal cancer cells via WNT signaling pathway

2020 ◽  
Author(s):  
Danyi Zhao ◽  
Bing Wang ◽  
Huawei Chen
Keyword(s):  
Esophageal Cancer ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Small Gtpases ◽  
Migration And Invasion ◽  
Cellular Functions ◽  
In Vivo Experiments ◽  
Ec Cells

Esophageal cancer (EC) recently has become a common malignancy of digestive system worldwide. RAB11A is a critical member of the small GTPases superfamily and was reported to affect a variety of cellular functions. However, its potential effects on EC progression and the specific regulatory mechanisms are still unclear. In this study, RAB11A was upregulated in human EC tissues and cells and predicted poor diagnosis. RAB11A expression was correlated with clinical-pathological features including pTNM stage (P=0.001*) and recurrence (P=0.000**) in patients with EC. Furthermore, RAB11A knockdown decreased the proliferation, migration, and invasion of EC cells via WNT pathway in vitro. Subsequently, the in vivo experiments confirmed that RAB11A contributed to EC tumor growth via WNT pathway. Therefore, these results provided evidence showing that RAB11A could promote the progression of EC via WNT pathway and might serve as a promising therapeutic target for EC treatment.

Transcription factor STAT1 promotes the proliferation, migration and invasion of nasopharyngeal carcinoma cells by upregulating LINC01160

2020 ◽  
Author(s):  
Jingang Ai ◽  
Guolin Tan ◽  
Tiansheng Wang ◽  
Wei Li ◽  
Ru Gao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nasopharyngeal Carcinoma ◽  
Chromatin Immunoprecipitation ◽  
Malignant Cell ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Cell Phenotype

Aim: To investigate the role of LINC01160 in nasopharyngeal carcinoma (NPC). Materials & methods: Using NPC cells CNE-2 and HNE-2 in vitro, we performed quantitative PCR to determine mRNA expression and western blotting to determine protein expression. CCK-8, transwell, flow cytometry and wound healing assays were done to examine the function of LINC01160 and STAT1. Chromatin immunoprecipitation PCR (ChIP-PCR) confirmed that STAT1 combines with the LINC01160 promoter region. Xenograft experiments were used to verify the role of STAT1 and LINC01160 in vivo. Results: LINC01160 is upregulated in NPC and can promote a malignant cell phenotype. STAT1 is a transcription factor of LINC01160 and can promote a malignant cell phenotype through upregulating LINC01160 expression. Conclusion: STAT1 can promote a malignant cell phenotype by upregulating LINC01160.

scholarly journals LncRNA APTR Promotes Uterine Leiomyoma Cell Proliferation by Targeting ERα to Activate the Wnt/β-Catenin Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Weiqiang Zhou ◽  
Guocheng Wang ◽  
Bilan Li ◽  
Junjie Qu ◽  
Yongli Zhang
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Uterine Leiomyoma ◽  
Laser Scanning ◽  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Laser Scanning Confocal Microscopy

The molecular mechanisms by which uterine leiomyoma (UL) cells proliferate are unclear. Long noncoding RNA (lncRNA) is reported to participate in the occurrence and development of gynecological cancers. We investigated the molecular mechanisms that lncRNA uses in UL. We found that lncRNA Alu-mediated p21 transcriptional regulator (APTR) showed higher expression in UL tumor tissues compared with that in normal uterine tissues. APTR induced cell proliferation and colony formation both in vitro and in vivo. The JASPAR database showed that APTR was likely interacted with ERα, and these molecules were identified via laser scanning confocal microscopy and RNA immunoprecipitation analysis. To verify the correlation between APTR and ERα, we overexpressed and underexpressed APTR and simultaneously expressed ERα. The results showed that APTR function was suppressed. APTR increased the expressions of the proteins in the Wnt pathway, and inhibiting ERα eliminated these responses. In conclusion, our data suggest that APTR promoted leiomyoma cell proliferation through the Wnt pathway by targeting ERα, suggesting a new role of APTR in the Wnt signaling pathway in UL.

scholarly journals Overexpression of ICAT Inhibits the Progression of Colorectal Cancer by Binding with β-Catenin in the Cytoplasm

2021 ◽  
Vol 20 ◽  
pp. 153303382110412
Author(s):  
Jiancong Hu ◽  
Zihan Wang ◽  
Junxiong Chen ◽  
Zhaoliang Yu ◽  
Jingdan Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Transcriptional Activity ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
T Cell Factor

Inhibitor of β-catenin and T-cell factor (ICAT) was first found as a polypeptide that blocks β-catenin–TCF interaction. Abundant evidence has shown that ICAT has different functions in diverse cancers’ progression. Nevertheless, the roles it plays in colorectal cancer (CRC) have not been described. Here, we documented that ICAT expression was higher in CRC tissue than in the adjacent normal tissue and that prognosis was better in high-ICAT expression patients. The overexpression of ICAT inhibited CRC cell proliferation both in vitro and in vivo. Wnt pathway transcriptional activity was suppressed in the CRC cells with ICAT overexpression, where the CCND1 and MYC expression, which occurs downstream of the Wnt signaling pathway, was inhibited. Co-immunoprecipitation experiments showed that ICAT bound with β-catenin in stable overexpression cell lines; immunofluorescence showed the co-localization of ICAT and β-catenin in the cytoplasm. Overall, our study reveals that ICAT inhibits CRC cell proliferation by binding to cytoplasm-located β-catenin, and prevents its translocation, which results in Wnt signaling pathway inactivation. It may provide a scientific foundation for focusing on ICAT in treatments for CRC.

scholarly journals The Notch Intracellular Domain Can Function as a Coactivator for LEF-1

2001 ◽  
Vol 21 (22) ◽  
pp. 7537-7544 ◽  
Author(s):  
David A. Ross ◽  
Tom Kadesch
Keyword(s):  
Notch Signaling ◽  
Wnt Signaling Pathway ◽  
Notch Pathway ◽  
High Mobility ◽  
In Vitro Assays ◽  
Transactivation Domain ◽  
Intracellular Domain ◽  
Notch Intracellular Domain

ABSTRACT Notch signaling commences with two ligand-mediated proteolysis events that release the Notch intracellular domain, NICD, from the plasma membrane. NICD then translocates into the nucleus and interacts with the DNA binding protein CSL to activate transcription. We found that NICD expression also potentiates activity of the transcription factor LEF-1. NICD stimulation of LEF-1 activity was context dependent and occurred on a subset of promoters distinct from those activated by β-catenin. Importantly, the effect of NICD does not appear to be mediated through canonical components of the Wnt signaling pathway or downstream components of the Notch pathway. In vitro assays show a weak association between the C-terminal transactivation domain of NICD and the high-mobility group domain of LEF-1, suggesting that the two proteins interact in vivo. Our data therefore describe a new nuclear target of Notch signaling and a new coactivator for LEF-1.

scholarly journals Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cell Biology ◽  
Wnt Pathway ◽  
Ectopic Expression ◽  
Homeobox Genes ◽  
Cell Phenotype

Abstract Background Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma. Methods Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo. Results In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors. Conclusions Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.

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