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Results for “Wnt Signaling Pathway”

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PubMed2004

[Anti-oncogene p53-induced expression of secreted frizzled-related protein, a Wnt signaling inhibitor].

OBJECTIVE: To investigate the effects of anti-oncogene p53 on the expression of secreted frizzled-related protein (sFRP), a Wnt pathway inhibitor. METHODS: Human hepatocarcinoma Hep3B cells were transfected with a replication-defective adenovirus encoding p53 (Adp53), and Adp53 transgene expression was measured by fluorescence-activated cell sorting (FACS) and sFRP mRNA expression detected by reverse transcriptional (RT)-PCR. RESULTS: sFRP mRNA expression in Hep3B cells was potentiated 20 h after the transfection with Adp53, reaching the peak level at 32 h. Dose-effect studies revealed that Adp53 at the doses of 0.5, 5 and 50 pfu/cell could promote the expression of sFRP mRNA, with the highest expression occurred with the dose of 5 pfu/cell. CONCLUSION: Ectogenetic p53 promotes mRNA expression of Wnt signaling pathway inhibitor sFRP in Hep3B cells.

Animals↗

PubMed2002

Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2.

We have isolated the entire coding sequence of human FRAT2 (frequently rearranged in advanced T-cell lymphomas-2). It exhibits appreciable amino acid identity to FRAT1 (77%) which was initially isolated as frequently being overexpressed in a murine leukemia virus insertion model in murine tumors. FRAT proteins are thought to play a role in Wnt signaling. They can bind to glycogen synthase kinase-3 (GSK-3) and Dishevelled, two proteins involved in Wnt signal transduction. Both hFRAT1 and hFRAT2 are intronless genes localized to the same portion of chromosome 10q24.1 and separated by only 10.7 kb. In a broad range of human tissues FRAT1 and FRAT2 are readily detected and expressed in a near identical pattern. Both species are repressed when the human embryonal carcinoma cell line, NT2/D1, is induced to differentiate with all-trans retinoic acid (RA). This treatment had no appreciable effect on FRAT levels in two other RA-sensitive cell lines that were not of germ cell tumor origin. The overlapping expression patterns suggest these two genes share a regulatory region. Both FRAT genes exhibited three species of mRNA, which varied in representation between tissues. When transiently overexpressed in COS-1 cells, the FRAT proteins were detected in the cytosol and concentrated in the nucleus. Both hFRAT1 and hFRAT2 are implicated in the selective modulation of GSK-3 activity via the Wnt signaling pathway. This study provides a foundation from which to examine the role these proteins play in Wnt-dependent and -independent processes.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Subcellular localization of beta-catenin and cadherin expression in the cap-stage enamel organ of the mouse molar.

We analyzed the subcellular distribution of beta-catenin in the cap-stage enamel organ and compared it with the expression of E- and P-cadherin by using confocal laser microscopy. The amounts of the molecules in the cytoplasm and the nucleus showed regional variations in the enamel organ, whereas cell surface-associated beta-catenin was ubiquitous. In both the enamel knot and the inner dental epithelium, beta-catenin was detected in the cytoplasm and in the nucleus. However, the amount of nuclear beta-catenin was apparently higher in the enamel knot than in the inner dental epithelium. P-cadherin also gave a stronger signal in the enamel knot than in other parts of the enamel organ. In the stellate reticulum, where E-cadherin was preferentially expressed, as well as in the cervical loop and outer dental epithelium, beta-catenin was localized in the cytoplasm but not in the nucleus. The nuclear localization of beta-catenin in the enamel knot suggests a specific activation of the canonical Wnt signaling pathway. A coincident upregulation of P-cadherin was observed in this area. Altogether, these observations suggest the possibility of a linkage between cell adhesion and Wnt signaling in the enamel knot.

Animals↗

PubMed1998

Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways.

The integrin-linked kinase (ILK) is an ankyrin repeat containing serine-threonine protein kinase that can interact directly with the cytoplasmic domains of the beta1 and beta3 integrin subunits and whose kinase activity is modulated by cell-extracellular matrix interactions. Overexpression of constitutively active ILK results in loss of cell-cell adhesion, anchorage-independent growth, and tumorigenicity in nude mice. We now show that modest overexpression of ILK in intestinal epithelial cells as well as in mammary epithelial cells results in an invasive phenotype concomitant with a down-regulation of E-cadherin expression, translocation of beta-catenin to the nucleus, formation of a complex between beta-catenin and the high mobility group transcription factor, LEF-1, and transcriptional activation by this LEF-1/beta-catenin complex. We also find that LEF-1 protein expression is rapidly modulated by cell detachment from the extracellular matrix, and that LEF-1 protein levels are constitutively up-regulated at ILK overexpression. These effects are specific for ILK, because transformation by activated H-ras or v-src oncogenes do not result in the activation of LEF-1/beta-catenin. The results demonstrate that the oncogenic properties of ILK involve activation of the LEF-1/beta-catenin signaling pathway, and also suggest ILK-mediated cross-talk between cell-matrix interactions and cell-cell adhesion as well as components of the Wnt signaling pathway.

Animals↗

PubMed2006

Genomic and post-genomic approaches to polycystic ovary syndrome--progress so far: Mini Review.

Genomic studies in polycystic ovary syndrome (PCOS) have focused on ovarian tissues and gene expression changes related to the gynaecological manifestations of PCOS. These studies have revealed a variety of altered genes that fall into many functional categories. Of these, the genes involved in steroidogenesis, including genes related to retinoic acid biosynthesis and LH-stimulated gene pathways, are generally up-regulated in PCOS samples. Genes involved in the Wnt signalling pathway appear down-regulated. Immune response genes and those involved in apoptosis are altered, but the net effect of these alterations is unclear at present. However, these altered gene expression patterns are yet to produce a defined aetiological basis or diagnostic biomarker for PCOS. The use of proteomic technologies for the study of the PCOS proteome is in its infancy; however, a few pilot studies have been published and the data are reviewed. Proteomics looks directly at the functional units within a cell, the proteins. This approach should thus serve to validate some of the gene expression changes identified and then build on the genomic results collected to date.

DNA↗

PubMed2006

Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal.

Duplin was originally isolated as a negative regulator of beta-catenin-dependent T-cell factor (Tcf) transcriptional activity in the Wnt signaling pathway. However, Duplin knockout mice exhibit embryonic lethality at 5.5-em day, suggesting that Duplin has important roles other than as a negative regulator of the Wnt signal. To identify new roles of Duplin, the Duplin-binding proteins were screened. PIAS3, which is a SUMO E3 ligase and acts as an inhibitor of signal transducer and activator of transcription (STAT3), was identified as a Duplin-binding protein. Duplin was sumoylated, but PIAS3 affected neither the sumoylation of Duplin nor its ability to inhibit Tcf-4 activity. Like PIAS3, Duplin suppressed the leukemia-inhibitory factor (LIF)-induced STAT3 transcriptional activity. Duplin did not affect the LIF-dependent tyrosine phosphorylation or nuclear localization of STAT3 but inhibited the formation of complex between STAT3 and DNA. Although STAT3 is not modified with SUMO, PIAS3 inhibited the STAT3 activity in a manner partially depending on its SUMO E3 ligase activity. Duplin suppressed the LIF-dependent STAT3 activity independently of sumoylation. These results demonstrate that Duplin inhibits not only Tcf-4 but also STAT3, suggesting that Duplin may act as a repressor for multiple transcriptional factors.

Animals↗

PubMed2025

HPV as a Molecular Hacker: Computational Exploration of HPV-Driven Changes in Host Regulatory Networks.

Human Papillomavirus (HPV), particularly high-risk strains such as HPV16 and HPV18, is a leading cause of cervical cancer and a significant risk factor for several other epithelial malignancies. While the oncogenic mechanisms of viral proteins E6 and E7 are well characterized, the broader effects of HPV infection on host transcriptional regulation remain less clearly defined. This study explores the hypothesis that conserved genomic motifs within the HPV genome may act as molecular decoys, sequestering human transcription factors (TFs) and thereby disrupting normal gene regulation in host cells. Such interactions could contribute to oncogenesis by altering the transcriptional landscape and promoting malignant transformation.We conducted a computational analysis of the genomes of high-risk HPV types using MEME-ChIP for de novo motif discovery, followed by Tomtom for identifying matching human TFs. Protein-protein interactions among the predicted TFs were examined using STRING, and biological pathway enrichment was performed with Enrichr. The analysis identified conserved viral motifs with the potential to interact with host transcription factors (TFs), notably those from the FOX, HOX, and NFAT families, as well as various zinc finger proteins. Among these, SMARCA1, DUX4, and CDX1 were not previously associated with HPV-driven cell transformation. Pathway enrichment analysis revealed involvement in several key biological processes, including modulation of Wnt signaling pathways, transcriptional misregulation associated with cancer, and chromatin remodeling. These findings highlight the multifaceted strategies by which HPV may influence host cellular functions and contribute to pathogenesis. In this context, the study underscores the power of in silico approaches for elucidating viral-host interactions and reveals promising therapeutic targets in computationally predicted regulatory network changes.

Humans↗

PubMed2005

Wnt-5a gene expression in malignant human neuroblasts.

Neuroblastoma (NB), an embryonal malignancy, poses a major challenge in pediatric oncology for the treatment of disseminated forms. Here, we report the decrease of Wnt-5a gene expression in high-risk NB (HR-NB) as well as in cultured metastatic neuroblasts. Wnt-5a is a member of the Wnt signaling pathway which is mainly associated with patterning decisions in the embryonic nervous system. Moreover, Wnt-5a has been involved in metastatic melanoma progression and invasive ductal breast cancer via adhesion and migration alterations. As retinoic acid (RA) plays a major role in the neural crest induction and differentiation, we showed that RA reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts. While beta-catenin expression remained unchanged, PKC-theta, a protein kinase C isoform, was evidenced to increase and parallel Wnt-5a level. For the first time, the involvement of Wnt-5a through the Wnt/calcium signaling is highlighted in the pathogenesis of a pediatric embryonal malignancy, NB.

Cell Differentiation↗

PubMed2006

Multiple redundant Wnt signaling components function in two processes during C. elegans vulval development.

In Caenorhabditis elegans, vulval precursor cell (VPC) fate is specified by the action of RTK/Ras, Notch and Wnt signaling pathways. While the identity of signals for the Ras and Notch pathways is known, the source and identity of the Wnt ligand acting on the VPCs are unknown. Single mutations in any of the five Wnt genes (lin-44, cwn-1, cwn-2, egl-20 and mom-2) do not cause strong defects in VPC fate specification, suggesting that functionally redundant Wnts are required. Surprisingly, we found that all five Wnts influence VPC fate. The strongest defects we observed were in the lin-44; cwn-1; egl-20 triple mutant. Anterior VPCs were more strongly affected by loss of Wnt function than posterior VPCs, and expression from WntColon, two colonsGFP transcriptional reporters showed that the Wnts most strongly affecting VPC fate were expressed predominantly in the posterior, suggesting that some of the redundant Wnt ligands act over a distance to affect the VPCs. In addition to ligand redundancy, we found that at least three Wnt receptors, lin-17, mom-5 and mig-1, function in the VPCs. We also examined ligand and receptor function in another Wnt-mediated vulval process, the orientation of the P7.p lineage. Here, too, we found that four of five Wnt receptors can influence P7.p orientation, suggesting that a surprising amount of functional redundancy exists in Wnt signaling during C. elegans vulval induction.

Animals↗

PubMed2004

Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro.

PURPOSE: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC. EXPERIMENTAL DESIGN: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1-156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4. RESULTS: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with </=20% membranous expression (P = 0.002). Moreover, membranous sFRP4 expression (P = 0.04) was an independent predictor of relapse when modeled with Gleason score (P = 0.006), pathological stage (P = 0.002), and pre-operative prostate-specific antigen levels (P = 0.004). In addition, in vitro studies demonstrated a decrease in the proliferation rate of PC3 cells transfected with sFRP4 when compared with the control PC3-empty vector cells (P < 0.0001). Decreased levels of phosphorylated glycogen synthase kinase 3beta in PC3-sFRP4 cells suggested that this phenotype is mediated by the "Wnt/beta-catenin" pathway. CONCLUSIONS: These data suggest that sFRP4 expression may be prognostic for localized PC, potentially as a consequence of an inhibitory effect on PC cell proliferation.

Adolescent↗

PubMed2003

Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis.

BACKGROUND: Beta-catenin was discovered as a cytoskeletal protein, constituting a link between the cadherins to the actin cytoskeleton. Aside from this function, beta-catenin is a key effector molecule in the Wnt signaling pathway, serving as a downstream transcription factor. METHODS: In this study, we examined the influence of electroconvulsive seizures (ECS) on the expression of beta-catenin, as well as expression of Wnt-2, in rat hippocampus. Repeated administration of generalized seizures increased levels of beta-catenin immunoreactivity in the subgranular zone of the hippocampus. To assess the relationship of beta-catenin to cell division in the dentate gyrus of the adult rat hippocampus, colocalization of beta-catenin with a marker of cell division was examined. RESULTS: Beta-catenin immunoreactivity was consistently localized in newborn cells in this region, indicating a possible role in cell division and differentiation in adult hippocampus. We also found that ECS treatment significantly increased levels of Wnt-2, one of the ligands that activates beta-catenin signaling. CONCLUSIONS: These results demonstrate that ECS increases Wnt-beta-catenin signaling and suggest that this pathway could mediate in part the neuronal adaptations underlying the therapeutic action of this treatment paradigm.

Animals↗

PubMed2005

Beta-catenin is essential for pancreatic acinar but not islet development.

Despite our increasingly sophisticated understanding of transcriptional regulation in pancreas development, we know relatively little about the extrinsic signaling pathways involved in this process. We show here that the early pancreatic epithelium exhibits a specific enrichment in unphosphorylated beta-catenin protein, a hallmark of activation of the canonical Wnt signaling pathway. To determine if this pathway is functionally required for normal pancreas development, we have specifically deleted the beta-catenin gene in these cells. Pancreata developing without beta-catenin are hypoplastic, although their early progenitors appear normal and exhibit no premature differentiation or death. Surprisingly, and in marked contrast to its role in the intestine, loss of beta-catenin does not significantly perturb islet endocrine cell mass or function. The major defect of the beta-catenin-deficient pancreas is an almost complete lack of acinar cells, which normally comprise the majority of the organ. beta-Catenin appears to be cell-autonomously required for the specification of acinar cells, rather than for their survival or maintenance, as deletion of beta-catenin specifically in differentiated acinar cells has no effect. Thus, our data are consistent with a crucial role for canonical Wnt signals in acinar lineage specification and differentiation.

Animals↗

PubMed2002

Epidermal differentiation: transgenic/knockout mouse models reveal genes involved in stem cell fate decisions and commitment to differentiation.

Epidermal development and differentiation are similar processes and therefore the study of one is likely to provide insight into the other. The signaling cascades required for epidermal differentiation are largely unknown. Recent evidence, however, has implicated two proteins, p63 and c-Myc, in different stages of epidermal development and differentiation. p63 was shown to be required for embryonic epidermal development. Mice lacking p63 do not develop stratified epithelia and appendages suggesting a role for p63 in the commitment to squamous epithelial lineages. Subsequent stem cell fate decisions are required to form the different structures of stratified epithelia including hair follicles, sebaceous glands, and epidermis. Several genes of the Wnt signaling pathway have been implicated in this process, including c-Myc, a downstream target of the Wnt pathway. Interestingly, targeted overexpression of c-Myc in the basal layer of the epidermis results in an increase in sebaceous gland size and number at the expense of hair follicles. This suggests that c-Myc promotes differentiation of epidermal stem cells into sebaceous glands. In this review, we discuss transgenic/knockout mouse models that have provided evidence linking c-Myc and p63 to different stages of epidermal development and differentiation.

Animals↗

PubMed1995

Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos.

The dorsoventral axis is established early in Xenopus development and may involve signaling by Wnts, a family of Wnt1-protooncogene-related proteins. The protein kinase shaggy functions in the wingless/Wnt signaling pathway, which operates during Drosophila development. To assess the role of a closely related kinase, glycogen synthase kinase 3 beta (GSK-3 beta), in vertebrate embryogenesis, we cloned a cDNA encoding a Xenopus homolog of GSK-3 beta (XGSK-3 beta). XGSK-3 beta-specific transcripts were detected by Northern analysis in Xenopus eggs and early embryos. Microinjection of the mRNA encoding a catalytically inactive form of rat GSK-3 beta into a ventrovegetal blastomere of eight-cell embryos caused ectopic formation of a secondary body axis containing a complete set of dorsal and anterior structures. Furthermore, in isolated ectodermal explants, the mutant GSK-3 beta mRNA activated the expression of neural tissue markers. Wild-type XGSK-3 beta mRNA suppressed the dorsalizing effects of both the mutated GSK-3 beta and Xenopus dishevelled, a proposed upstream signaling component of the same pathway. These results strongly suggest that XGSK-3 beta functions to inhibit dorsoventral axis formation in the embryo and provide evidence for conservation of the Wnt signaling pathway in Drosophila and vertebrates.

Amino Acid Sequence↗

PubMed2006

STMN2 is a novel target of beta-catenin/TCF-mediated transcription in human hepatoma cells.

The activity of beta-catenin/TCF, the key component of Wnt signaling pathway, is frequently deregulated in human cancers, resulting in the activation of genes whose dysregulation has significant consequences on tumor development. Therefore, identifying the target genes of Wnt signaling is important for understanding beta-catenin-mediated carcinogenesis. Here, we report STMN2, a gene implicated in the regulation of microtubule dynamics, as a novel target of beta-catenin-mediated transcription. STMN2 was up-regulated in hepatoma and cirrhotic liver tissues compared to normal liver and also in cell lines where beta-catenin/TCF is constitutively activated. Transient activation of beta-catenin/TCF either by transfection of a constitutively active form of beta-catenin or by LiCl treatment induced the STMN2 mRNA expression in PLC/PRF/5 cells. Of the four members of STMN gene family, only STMN2 showed a Wnt-dependent expression pattern. Through promoter mapping and chromatin immunoprecipitation assays, we found that STMN2 is a direct target of beta-catenin/TCF-mediated transcription and that the TCF binding site at -1713 of STMN2 promoter is critical for beta-catenin/TCF-dependent expression regulation. siRNA-mediated knock-down of STMN2 expression indicated that STMN2 is required for maintaining the anchorage-independent growth state of beta-catenin/TCF-activated hepatoma cells. Our results suggest that STMN2 might be a novel player of beta-catenin/TCF-mediated carcinogenesis in the liver.

Carcinoma, Hepatocellular↗

PubMed2006

Wnt-10b secreted from lymphocytes promotes differentiation of skin epithelial cells.

Wnt-10b was originally isolated from lymphoid tissue and is known to be involved in a wide range of biological actions, while recently it was found to be expressed early in the development of hair follicles. However, few studies have been conducted concerning the role of Wnt-10b with the differentiation of skin epithelial cells. To evaluate its role in epithelial differentiation, we purified Wnt-10b from the supernatant of a concanavalin A-stimulated lymphocyte culture using an affinity column and investigated its effects on the differentiation of adult mouse-derived primary skin epithelial cells (MPSEC). MPSEC cultured with Wnt-10b showed morphological changes from cuboidal to spindle-shaped with inhibited proliferation, and also obtained characteristics of the hair shaft and inner root sheath of the hair follicle, represented by red-colored Ayoub Shklar staining, and reactions to AE-13 and AE-15 as seen with immunocytology. Further, RT-PCR analysis demonstrated the expression of mRNA for keratin 1, keratin 2, loricrin, mHa5, and mHb5, in association with a decreased expression of the basal cell marker keratin 5, in Wnt-10b-treated MPSEC. In addition, involvement of the canonical Wnt signal pathway was demonstrated by a TCF reporter (pTOPFLASH) assay. These results suggest that Wnt-10b promotes the differentiation of MPSEC and may play an important role in hair follicle development by promoting differentiation of epithelial cells.

Animals↗

PubMed2005

Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland.

Key gene families such as FGFs and BMPs are important mediators of branching morphogenesis. To understand whether Wnt genes, and in particular, the canonical Wnt signaling pathway also function in the branching process, we have used a combination of experimental and genetic gain and loss of function approaches to perturb the levels of canonical Wnt signaling in two arborized structures, the lung and the lacrimal gland. Here, we show that the addition of Wnt3a conditioned medium or LiCl strongly represses growth and proliferation of the lung and lacrimal gland, a result that was confirmed in vivo using a dominant stable mutation of beta-catenin conditionally expressed in the lacrimal gland epithelium. In agreement with these data, knockdown of Wnt signaling with beta-catenin morpholinos results in a greater number of branches and increased cell proliferation. In addition, we show that canonical Wnt signaling is able to modulate the levels of Fgf10 and suppress BMP-induced proliferation in the lacrimal gland. Thus, canonical Wnt signaling negatively regulates branching morphogenesis providing a balance to FGFs and BMPs which positively regulate this process. This multilayered control of growth and proliferation ensures that branched structures attain the morphology required to function efficiently.

Adherens Junctions↗

PubMed2005

Maternal XTcf1 and XTcf4 have distinct roles in regulating Wnt target genes.

Wnt signaling pathways have essential roles in developing embryos and adult tissue, and alterations in their function are implicated in many disease processes including cancers. The major nuclear transducers of Wnt signals are the Tcf/LEF family of transcription factors, which have binding sites for both the transcriptional co-repressor groucho, and the co-activator beta-catenin. The early Xenopus embryo expresses three maternally inherited Tcf/LEF mRNAs, and their relative roles in regulating the expression of Wnt target genes are not understood. We have addressed this by using antisense oligonucleotides to deplete maternal XTcf1 and XTcf4 mRNAs in oocytes. We find that XTcf1 represses expression of Wnt target genes ventrally and laterally, and activates their expression dorsally. Double depletions of XTcf1 and XTcf3 suggest that they act cooperatively to repress Wnt target genes ventrally. In contrast, XTcf4 has no repressive role but is required to activate expression of Xnr3 and chordin in organizer cells at the gastrula stage. This work provides evidence for distinct roles for XTcfs in regulating Wnt target gene expression.

Animals↗