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Results for “Wnt Signaling Pathway”

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PubMed2001

Constitutive activation of the Wnt signaling pathway by CTNNB1 (beta-catenin) mutations in a subset of human lung adenocarcinoma.

Constitutive activation of the Wnt signaling pathway as a result of genetic alterations of APC, AXIN1, and CTNNB1 has been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. To investigate the pathogenetic significance of constitutive activation of the Wnt signaling pathway in human lung carcinogenesis, CTNNB1 alterations in exon 3, a region known to represent a mutation hot spot, were screened in 46 lung cancer cell lines and 47 primary lung cancers. Missense mutations causing substitutions of Ser/Thr residues critical for regulation by GSK-3beta were detected in one (2%) of the cell lines, A427, and two (4%) of the surgical specimens. The three lung cancers with CTNNB1 mutations were adenocarcinomas. To explore the prevalence of constitutive activation of the Wnt signaling pathway in human lung cancer, we assessed 15 lung cancer cell lines representing major histological subtypes of lung cancers for constitutive Tcf transcriptional activity (CTTA). CTTA was observed only in the A427 adenocarcinoma cell line, but not in the remaining 14 cell lines. The data indicate that constitutive activation of the Wnt signaling pathway caused by CTNNB1 mutation is involved in the development and/or progression of a subset of lung carcinoma, preferentially in adenocarcinoma.

Adenocarcinoma↗
PubMed2002

An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder.

The Wnt-signalling pathway has been implicated in a variety of processes including cortical development and plasticity. We have previously demonstrated a reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal cortex in schizophrenia and aimed to further elucidate the abnormalities of the Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting was performed to quantify the levels of three members of the Wnt-signalling pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder and in matched controls. We found no significant differences between the disease and control groups for any of the proteins studied, and therefore, cannot confirm our earlier findings of abnormalities of GSK-3beta in schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway.

Hepatic adenomas are strongly linked to excess hormonal exposure, but little else is known about their pathogenesis. The Wnt signaling pathway, which is activated in both hepatocellular carcinomas and hepatoblastomas, has not been studied in hepatic adenomas. Fifteen hepatic adenomas were studied by immunohistochemistry for estrogen, progesterone, and androgen receptors (ER, PR, AR, respectively) and correlated with the results of immunostaining for beta-catenin. Direct sequencing was performed to look for mutations in key genes involved in the Wnt signaling pathway: Exon 3 of beta-catenin encompassing the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation region and the mutational cluster region of the adenomatosis polyposis coli protein (APC). Analysis for loss of heterozygosity (LOH) at chromosome 5q was also performed. Immunostaining for both ER and PR was present in 11/15 (73%) adenomas, and staining with one hormone receptor was positively associated with staining for the other receptor. AR positivity was present in 3/15 cases. Nuclear accumulation of beta-catenin was present in 7/15 (46%) of adenomas, indicating activation of the Wnt signaling pathway. However, no beta-catenin mutations, no APC mutations in the mutational cluster region, and no 5q LOH were detected. Two APC polymorphisms of unknown significance were seen. No clear association between beta-catenin nuclear accumulation and hormone receptor positivity was discerned. Activation of the Wnt signaling pathway appears to be important in a subset of hepatic adenomas but does not result from common beta-catenin or APC mutations and does not appear to be directly linked to hormonal receptor status.

Adenoma, Liver Cell↗
PubMed2006

Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells.

WNT, Notch, FGF, and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. Association of Notch ligands with Notch receptors on neighboring cells leads to cleavage of Notch receptors by metalloprotease and gamma-secretase to induce nuclear translocation of Notch intracellular domain (NICD). Nuclear complex, consisting of CSL (RBPSUH), NICD, Mastermind (MAML), p300 and histone acetyltransferase (HAT), then induces transcriptional activation of Notch target genes, such as HES1, HES5, HES7, HEY1, HEY2 and HEYL. Here, we searched for TCF/LEF-binding site within the promoter region of Notch ligand genes, including DLL1, DLL3, DLL4, JAG1 and JAG2. Because TCF/LEF-binding sites were identified within human JAG1 promoter based on bioinformatics and human intelligence, comparative genomics analyses on JAG1 orthologs were further performed. Chimpanzee JAG1 gene, consisting of 26 exons, was identified within NW_120319.1 genome sequence. XM_525264.1 and XM_514517.1 were not the correct coding sequences for chimpanzee JAG1. Chimpanzee JAG1 gene was found to encode a 1218-amino-acid protein showing 99.5% and 96.2% total-amino-acid identity with human JAG1 and mouse Jag1, respectively. Phylogenetic analysis revealed that JAG1 orthologs were more conserved than those of other Notch ligands. JAG1 gene was identified as evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian JAG1 orthologs. Human JAG1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, lung carcinoid, gastric cancer, pancreatic cancer, colon cancer, and also in squamous cell carcinoma (SCC) of skin, oral cavity, esophagus, head and neck. JAG1 expression on progenitor cells due to canonical WNT signaling activation induces self-renewal of stem cells due to Notch signaling activation. JAG1, functioning as WNT-dependent Notch signaling activator, is the key molecule maintaining the homeostasis of stem and progenitor cells.

Amino Acid Sequence↗
PubMed2007

WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates.

Notch and WNT signaling pathways are key components of the stem cell signaling network. Canonical WNT signaling to intestinal progenitor cells leads to transcriptional activation of the JAG1 gene, encoding Serrate-type Notch ligand. JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD). NICD is associated with CSL/RBPSUH and Mastermind (MAML1, MAML2, or MAML3) to activate Notch target genes, such as HES1 and HES5. Although WNT-dependent Notch signaling activation in intestinal stem cells is clarified, the effects of Notch signaling activation on WNT signaling in progenitor cells remain unclear. We searched for Notch-response element (NRE) in the promoter region of genes encoding secreted WNT signaling inhibitors, including DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1. Double NREs were identified within human DKK2 promoter by bioinformatics and human intelligence (Humint). The human DKK2 gene was characterized as Notch signaling target in intestinal stem cells. Because DKK2 is a key player in the stem cell signaling network, the DKK2 gene at human chromosome 4q25 is a candidate tumor suppressor gene inactivated due to epigenetic silencing and/or deletion. The chimpanzee DKK2 gene was identified within the NW_105990.1 genome sequence, while the cow Dkk2 gene was identified within the AC156664.2 and AC158038.2 genome sequences. Chimpanzee DKK2 and cow Dkk2 showed 98.5% and 95.8% total-amino-acid identity with human DKK2, respectively. Double NREs in human DKK2 promoter were conserved in chimpanzee DKK2 promoter, partially in rat Dkk2 promoter, but not in cow and mouse Dkk2 promoters. The Notch-DKK2 signaling loop, created or potentiated in primates, was complementary to WNT-DKK1 and BMP-IHH-SFRP1 signaling loops for negative regulation of canonical WNT signaling pathway. Together, these facts indicate that DKK2 promoter evolution resulted in the augmentation of a WNT negative regulation system in primates.

Amino Acid Sequence↗
PubMed2000

Cross-regulation of the Wnt signalling pathway: a role of MAP kinases.

The Wnt signal transduction pathway regulates various aspects of embryonal development and is involved in cancer formation. Wnts induce the stabilisation of cytosolic (beta)-catenin, which then associates with TCF transcription factors to regulate expression of Wnt-target genes. At various levels the Wnt pathway is subject to cross-regulation by other components. Recent evidence suggests that a specific MAP kinase pathway involving the MAP kinase kinase kinase TAK1 and the MAP kinase NLK counteract Wnt signalling. In particular, homologues of TAK1 and NLK, MOM-4 and LIT-1, negatively regulate Wnt-controlled cell fate decision in the early Caenorhabditis elegans embryo. Moreover, TAK1 activates NLK, which phosphorylates TCFs bound to (beta)-catenin. This blocks nuclear localization and DNA binding of TCFs. Since TAK1 is activated by TGF-(beta) and various cytokines, it might provide an entry point for regulation of the Wnt system by other pathways. In addition, alterations in TAK1-NLK might play a role in cancer.

Animals↗
PubMed2001

Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase Iepsilon.

Although casein kinase Iepsilon (CKIepsilon) has been shown to regulate the Wnt signaling pathway positively, its mode of action is not clear. In this study we show that CKIepsilon activates the Wnt signaling pathway in co-operation with Dvl. CKIepsilon and Axin associated with different sites of Dvl, and CKIepsilon and Dvl interacted with distinct regions on Axin. Therefore, these three proteins formed a ternary complex. Either low expression of Dvl or CKIepsilon alone did not accumulate beta-catenin, but their co-expression accumulated greatly. Dvl and CKIepsilon activated the transcriptional activity of T cell factor (Tcf) synergistically. Although the Dvl mutant that binds to Axin but not to CKIepsilon activated Tcf, it did not synergize with CKIepsilon. Another Dvl mutant that does not bind to Axin did not activate Tcf irrespective of the presence of CKIepsilon. Furthermore, Dvl and CKIepsilon co-operatively induced axis duplication of Xenopus embryos. These results indicate that Dvl and CKIepsilon synergistically activated the Wnt signaling pathway and that the binding of the complex of Dvl and CKIepsilon to Axin is necessary for their synergistic action.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein.

In attempting to clarify the roles of Dvl in the Wnt signaling pathway, we identified a novel protein which binds to the PDZ domain of Dvl and named it Idax (for inhibition of the Dvl and Axin complex). Idax and Axin competed with each other for the binding to Dvl. Immunocytochemical analyses showed that Idax was localized to the same place as Dvl in cells and that expression of Axin inhibited the colocalization of Dvl and Idax. Further, Wnt-induced accumulation of beta-catenin and activation of T-cell factor in mammalian cells were suppressed by expression of Idax. Expression of Idax in Xenopus embryos induced ventralization with a reduction in the expression of siamois, a Wnt-inducible gene. Idax inhibited Wnt- and Dvl- but not beta-catenin-induced axis duplication. It is known that Dvl is a positive regulator in the Wnt signaling pathway and that the PDZ domain is important for this activity. Therefore, these results suggest that Idax functions as a negative regulator of the Wnt signaling pathway by directly binding to the PDZ domain of Dvl.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm.

WNT signaling plays a major role in patterning the dermomyotome of the somitic mesoderm. However, knowledge of downstream target genes and their regulation is limited. To identify new genes involved in the development and early patterning of the somite, we performed a comparison of gene expression by microarray between the presomitic mesoderm and the 5 most recently formed somites of the mouse at embryonic day 9.5. We identified 207 genes upregulated and 120 genes downregulated in somite formation. Expression analysis and functional categorization of these genes demonstrate this to be a diverse pool that provides a valuable resource for studying somite development. Thus far, we have found three genes expressed in the dermomyotome of the early somite. Consistent with their expression patterns, these genes are transcriptional targets of WNT signals, but display differential activation by different WNTs. We further demonstrate that 1 of these genes, Troy, is a direct target of canonical WNT signaling, while the other 2 genes, Selp and Arl4, are not. Thus, our microarray study using microdissected tissues not only provides global information on gene expression during somite development, it also provides novel targets to study the inductive signaling pathways that direct somite patterning.

Adenoviridae↗
PubMed2006

Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway.

Nasopharyngeal carcinoma (NPC) is a particularly common malignant disease in areas of south China and Southeast Asia. To characterize the gene expression profiling of NPC, we detected the gene expression profiles in 22 NPC and 10 nontumor nasopharyngeal epithelial tissues by complementary DNA microarray. We identified 503 genes that were significantly (P < .001) differentially regulated between NPC and nontumor nasopharyngeal epithelial tissues. The differentially expressed genes are involved in many signaling pathways, such as the Wnt, transforming growth factor-beta, and mitogen-activated protein kinase signaling pathways. The aberrant expression of the Wnt signaling pathway components, such as wingless-type MMTV integration site family, member 5A, Frizzled homolog 7, casein kinase IIbeta, beta-catenin, CREB-binding protein, and Dishevelled-associated activator of morphogenesis 2 was validated on the NPC tissue microarrays. The data suggest that the Wnt signaling pathway may be abnormally regulated in NPC, which provides insight into the molecular mechanisms of NPC.

Adolescent↗
PubMed2003

Tumor formation by genetic mutations in the components of the Wnt signaling pathway.

The genetics of development and cancer have converged in the identification of intra- and extra-cellular signaling pathways that are aberrantly regulated in cancer, and are also central to embryonic patterning. The Wnt signaling pathway has provided an outstanding example of this. The genes for beta-catenin, APC, and Axin in the Wnt signaling pathway are often mutated in human cancers. In all such cases, the common denominator is the activation of gene transcription by beta-catenin. The resulting gene expression profile should provide a significant clue to the developmental mechanisms of cancers carrying defects in the Wnt signaling pathway. In this review, the functions of beta-catenin, APC and Axin, and the alterations of the three genes in human cancers are described.

Axin Protein↗
PubMed2002

Ligand receptor interactions in the Wnt signaling pathway in Drosophila.

Secreted Wnt proteins have numerous signaling functions during development, mediated by Frizzled molecules that act as Wnt receptors on the cell surface. In the genome of Drosophila, seven Wnt genes (including wingless; wg), and five frizzled genes have been identified. Relatively little is known about signaling and binding specificities of different Wnt and Frizzled proteins. We have developed an assay to determine the strength of binding between membrane-tethered Wnts and ligand binding domains of the Frizzled receptors. We found a wide spectrum of binding affinities, reflecting known genetic interactions. Most Wnt proteins can bind to multiple Frizzleds and vice versa, suggesting redundancy in vivo. In an extension of these experiments, we tested whether two different subdomains of the Wg protein would by themselves bind to Frizzled and generate a biological response. Whereas these two separate domains are secreted from cells, suggesting that they form independently folded parts of the protein, they were only able to evoke a response when co-transfected, indicating that both are required for function. In addition to the Frizzleds, members of the LRP family (represented by the arrow gene in Drosophila) are also necessary for Wnt signal transduction and have been postulated to act as co-receptors. We have therefore examined whether a soluble form of the Arrow molecule can bind to Wingless and Frizzled, but no interactions were detected.

Amino Acid Sequence↗
PubMed2001

Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A.

Axin, a negative regulator of the Wnt signaling pathway, forms a complex with glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, adenomatous polyposis coli (APC) gene product, and Dvl, and it regulates GSK-3beta-dependent phosphorylation in the complex and the stability of beta-catenin. Using yeast two-hybrid screening, we found that regulatory subunits of protein phosphatase 2A, PR61beta and -gamma, interact with Axin. PR61beta or -gamma formed a complex with Axin in intact cells, and their interaction was direct. The binding site of PR61beta on Axin was different from those of GSK-3beta, beta-catenin, APC, and Dvl. Although PR61beta did not affect the stability of beta-catenin, it inhibited Dvl- and beta-catenin-dependent T cell factor activation in mammalian cells. Moreover, it suppressed beta-catenin-induced axis formation and expression of siamois, a Wnt target gene, in Xenopus embryos, suggesting that PR61beta acts either at the level of beta-catenin or downstream of it. Taken together with the previous observations that PR61 interacts with APC and functions upstream of beta-catenin, these results demonstrate that PR61 regulates the Wnt signaling pathway at various steps.

Animals↗
PubMed2004

Interactions between BMP and Wnt signaling pathways in mammalian cancers.

The bone morphogenetic protein (BMP) and Wnt signaling pathways have been extensively studied in the regulation of early embryonic development and in the control of cell proliferation in adult tissues. Genetic interaction between these highly conserved and ubiquitous signaling pathways has been observed in multiple settings in fruit flies, amphibians, zebrafish, and mammals. While the importance of Wnt signaling in carcinogenesis has been well established, more recent work has also implicated BMP signaling in apoptosis and as a negative regulator of proliferation. In this issue of Cancer Biology & Therapy, Nishanian et al. extend these studies and propose interesting potential interactions between BMP and Wnt signaling in transformed mammalian cells that could have important implications for the control of human cancers.

Animals↗
PubMed2003

The human T-cell factor-4 gene splicing isoforms, Wnt signal pathway, and apoptosis in renal cell carcinoma.

beta-Catenin and transcriptional factor TCF-4 (human T-cell factor-4) genes comprise the Wnt signal. The Wnt signal pathway plays an important role in malignant transformation. We hypothesize that the beta-catenin and TCF-4 gene and Wnt signal are important in the progression of renal cell carcinoma (RCC). To test this hypothesis, we investigated TCF-4 splicing isoforms, beta-catenin, and Wnt signal pathway (cyclin D1, c-myc, c-jun, and MMP7) in three RCC cell lines (A498, Caki-1, and Caki-2), 38 primary RCCs, and 29 normal kidney samples. We also analyzed the relationship between TCF-4 gene splicing isoforms, proliferation (proliferating cell nuclear antigen labeling index), and apoptosis [antiapoptotic factors (Bcl-2 and Bcl-x(L)), proapoptotic factors (Bak and Bax), and caspase-3] in RCC samples. In 38 RCC samples, four splicing isoforms of the TCF-4 gene were present in the region between exon 12 and exon 17. Thirty (79%) of 38 RCCs and all (100%) of the normal kidney samples showed mixed isoforms with both long and short reading frames in the COOH-terminal region, whereas the remaining 8 RCC samples showed only the long-form reading frame. Two COOH-terminal-binding protein sites were present only in the long-form reading frame. The eight RCCs that demonstrated only the long reading frame isoform showed early disease progression and poor prognosis. In these 8 RCC samples, down-regulation of cyclin D1, c-myc, c-jun, and MMP7 expression was observed at the mRNA level. In addition, a marked reduction of caspase-3 expression was also found at both the mRNA and the protein level. However, the beta-catenin gene was not overexpressed at the mRNA level and protein level, and mutation and deletion were not observed in exon 3. In these three renal cell lines, there was no significant difference in TCF-4 mRNA expression before and after 5-Aza-2'-deoxycytidine treatment, and there appeared to be no splicing isoforms in the region between exon 1 and exon 11. These findings suggest that alteration in beta-catenin is an infrequent event in RCC. In samples in which beta-catenin was not overexpressed, the target genes of Wnt signal were regulated through TCF-4 splicing isoforms. The imbalance between TCF-4 gene splicing isoforms with long and short reading frames is associated with RCC progression through the inhibition of the apoptotic pathway. We demonstrate for the first time that TCF-4 gene splicing isoforms and the Wnt signal pathway can induce progression of RCC by the inhibition of apoptosis and not by the induction of cell proliferation.

Adult↗
PubMed2002

Axin, the main component of the Wnt signaling pathway, is not mutated in kidney tumors in children.

The Wnt signaling pathway is essential for embryonic development and can be involved in tumorigenesis when aberrantly activated. In a subset of Wilms' tumors, beta-catenin mutations have been identified, and this suggested that abnormally activated Wnt signaling may contribute to tumorigenesis of this tumor. Because Axin has been recognized as a main component of Wnt signaling, and its mutations were reported in several types of malignancies, we analyzed Axin gene mutations in 22 pediatric renal tumors. Twenty-four sets of the primers, which cover the whole coding region of the Axin gene, were used for PCR-SSCP analyses. Samples revealing aberrant band patterns were further analyzed for sequencing. We have only identified 4 silent mutations in the coding region and 3 intronic polymorphisms in Axin gene, accordingly no pathogenetic gene mutations were detected. Our results indicated that mutations of Axin gene as a mechanism of tumorigenesis are not associated with pediatric renal tumors including Wilms' tumors.

Axin Protein↗
PubMed2005

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner.

To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (ca) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of beta-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner.

Animals↗
PubMed2006

Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling.

A growing body of evidence implicates Wnt signaling in the control of angiogenesis. To better understand the role of the Wnt/beta-catenin pathway in endothelial cells (EC), we examined endogenous signaling activity and signaling component expression in vascular cells. We observed stabilization of cytosolic beta-catenin and activation of a T-cell factor (TCF) -luciferase promoter, hallmarks of canonical Wnt signaling activity, in cultured EC. This activity was increased in subconfluent EC, which are known to display characteristics of angiogenic EC, compared with confluent EC, which have a more differentiated phenotype. Endogenous TCF activity was inhibited by transfection with a secreted inhibitor of canonical Wnt signaling. A systematic analysis of Wnt, Fzd, SFRP, and Dkk gene expression in human EC (cultured and freshly isolated), smooth muscle cells (cultured), and aorta demonstrated that numerous Wnt signaling components are expressed by vascular cells. We conclude that Wnt signaling components are expressed and active in cultured EC.

Cell Movement↗