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Results for “Wnt Signaling Pathway”

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PubMed2006

Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice.

Hedgehog (Hh), Notch, and Wingless (Wnt) signaling control normal development of the cerebellum, and dysregulation of these signaling pathways are associated with medulloblastoma (MB). As an initial step in the study of the role of interacting signaling pathways in MB pathogenesis, we demonstrate the expression of several components of the Notch and Wnt signaling pathways, and activation of Notch signaling in MB from Ptch +/- mice that have elevated Hh signaling. We also show a marked downregulation in the expression of Notch2, Jagged1, Hes1, mSfrp1, and mFrz7 in cerebella of developing mice with reduced Hh signaling, suggesting that Hh signaling regulates the expression of these genes. Together with recent published data, these findings indicate that Hh signaling might synergize simultaneously with Notch and Wnt signaling in MB development by controlling Notch and Wnt pathway ligand, receptor and/or target gene expression.

Animals↗

PubMed2007

Complex expression pattern of Wnt ligands and frizzled receptors in human placenta and its trophoblast subtypes.

Canonical Wingless (Wnt) signalling provoked by exogenous and endogenous Wnt ligands was recently shown to play a crucial role in the invasive differentiation of human trophoblasts. To gain insights into the expression pattern of the developmental regulators, we analysed all human Wnt ligands and their frizzled (FZD) receptors in the human placenta and different trophoblast model systems using semi-quantitative PCR. Fourteen out of 19 Wnt ligands and 8 out of 10 FZD receptors were detectable in placental tissues, however, expression patterns varied with gestational age and between different trophoblast subtypes suggesting cell-specific functions. Besides Wnt ligands acting through the canonical pathway, non-canonical ligands such as Wnt-5a, which may also activate alternative Wnt signalling pathways or inhibit canonical Wnt signalling, could be identified. Western blot analyses revealed secretion of Wnt-5a from primary trophoblast cultures and trophoblastic cell lines. To evaluate the potential role of Wnt-5a, SGHPL-5 trophoblast cells were transfected with luciferase reporter plasmids harbouring eight T-cell factor (TCF) DNA-recognition sequences which are exclusively activated through the canonical Wnt signalling pathway. Luciferase assays revealed that Wnt-3a-induced reporter activity was repressed by recombinant Wnt-5a indicating an antagonistic role in trophoblasts. The data suggest that a complex network of Wnt ligands and FZD receptors may regulate developmental processes of the human placenta.

Cells, Cultured↗

PubMed2002

Molecular causes of colon cancer.

Cells in a developing embryo communicate with each other through a limited number of intercellular signalling pathways, of which the Wnt signalling pathway is one. Little is known about the function of Wnt signalling beyond that in embryogenesis. However, recent insights into the molecular etiology of colon cancer have implied a central role for the Wnt signalling pathway. The malignant transformation of colorectal epithelium is well defined, leading to adenoma and sequentially carcinoma formation. Several genes that regulate the Wnt pathway are mutated in cancer of the human colon and other organs. All of these mutations lead to the inappropriate activation of the pathway, which instructs the cell to divide unrestrictedly. These insights now allow the Wnt pathway to be exploited as a new target for drug development in colon cancer.

Adenomatous Polyposis Coli Protein↗

PubMed2006

The Wnt-dependent signaling pathways as target in oncology drug discovery.

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer's disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways.

Animals↗

PubMed2006

Wnt signaling activation during bone regeneration and the role of Dishevelled in chondrocyte proliferation and differentiation.

Wnt signaling is intrinsically involved in diverse cellular activities during cell differentiation, early embryonic development and organogenesis. Although much is known regarding the effects of Wnt signaling in the developing skeletal system, its role during regeneration remains unclear. Herein, we show transcriptional activation of specific members and target genes of the Wnt signaling pathway. Specifically, all of the Wnt signaling members and target genes analyzed were found to be upregulated during the early stages of fracture repair, with the exception of LEF1 whose expression was downregulated. In addition, spatial expression analysis of Dishevelled (Dvl) and beta-catenin in the fracture callus revealed an identical pattern of expression with both proteins localizing in osteoprogenitor cells of the periosteum, osteoblasts and proliferating/pre-hypertrophic chondrocytes. Further, in vitro knockdown of all three Dvl isoforms in chondrocytes using small interfering RNAs (siRNA) leads to partial inhibition of cell proliferation and differentiation, decreased expression of chondrogenic markers (ColII, ColX, Sox9) and suppressed nuclear accumulation of unphosphorylated beta-catenin. Taken together, these data verify our previous finding that the Wnt signaling pathway is activated during bone regeneration, by characterizing the temporal and spatial expression of a broad spectrum of Wnt-signaling molecules. Our data also suggest that all three Dvl isoforms, acting through the Wnt canonical pathway, are critical regulatory molecules for chondrocyte proliferation and differentiation.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Regulation of hematopoietic stem cell self-renewal.

Every day, billions of new blood cells are produced in the body, each one derived from a hematopoietic stem cell (HSC). Because most mature blood stem cells have a limited life span, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life. A key problem in hematopoietic stem cell biology is how HSC self-renewal is regulated. Recent evidence suggests that signaling pathways classically involved in embryonic development--such as the Wnt signaling pathway--play an important role in regulating stem cell self-renewal. The Wnt signaling pathway has been shown to regulate stem cell fate choice in a variety of organs, including the skin, the nervous system, and the hematopoietic system. In the hematopoietic system, stimulation of hematopoietic progenitors and stem cells with soluble Wnt proteins or downstream activators of the Wnt signaling pathway leads to their expansion. Future studies focusing on the mechanism of action of the Wnt signaling pathway and its interaction with other pathways are needed to gain further insight into the regulation of stem cell self-renewal, not only in the hematopoietic system but also in a variety of other tissues.

Animals↗

PubMedDate not supplied

Modulation of Wnt signaling by Axin and Axil.

The Wnt signaling pathway is conserved in various species from worms to mammals, and plays important roles in development, cellular proliferation, and differentiation. The molecular mechanisms by which the Wnt signal regulates cellular functions are becoming increasingly well understood. Wnt stabilizes cytoplasmic beta-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. Axin and its homolog Axil, newly recognized as components of the Wnt signaling pathway, negatively regulate this pathway. Other components of the Wnt signaling pathway, including Dvl, glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, and adenomatous polyposis coli (APC), interact with Axin, and the phosphorylation and stability of beta-catenin are regulated in the Axin complex. Axil has similar functions to Axin. Thus, Axin and Axil act as scaffold proteins in the Wnt signaling pathway, thereby modulating the Wnt-dependent cellular functions.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Engrailed-1 negatively regulates beta-catenin transcriptional activity by destabilizing beta-catenin via a glycogen synthase kinase-3beta-independent pathway.

The Wnt signaling pathway plays a major role in development, and upon deregulation it is implicated in neoplasia. The hallmark of the canonical Wnt signal is the protection of beta-catenin from ubiquitination and proteasomal degradation induced by glycogen synthase kinase (GSK)-3beta inhibition. The stabilized beta-catenin translocates to the nucleus where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes. In the absence of Wnt signal, TCF/LEF bind to Groucho (Gro)/TLE corepressors and repress Wnt target genes. Gro/TLE bind also to Engrailed (En) transcription factors mediating En-repressive activity on En target genes. Here, we present data suggesting that En-1 serves also as a negative regulator of beta-catenin transcriptional activity; however, its repressive effect is independent of Gro/TLE. Our data suggest that En-1 acts by destabilizing beta-catenin via a proteasomal degradation pathway that is GSK-3beta-independent. Moreover, because En-1-mediated beta-catenin degradation is also Siah independent, our data imply that En-1 exerts its repressive effect by a novel mechanism negatively controlling the level of beta-catenin.

Base Sequence↗

PubMed1998

sFRP-2 is a target of the Wnt-4 signaling pathway in the developing metanephric kidney.

Members of the Wnt family of secreted glycoproteins act as short-range signaling molecules in vertebrate embryogenesis. Previous work has shown that Wnt-4 is required for kidney development. Mice lacking functional Wnt-4 fail to form pretubular cell aggregates. Wnt-4 acts as an autoinducer of the mesenchymal to epithelial transition underlying nephron development. We have identified a member of the gene family encoding secreted frizzled related proteins (sFRP), putative Wnt antagonists, that shows overlapping expression with Wnt-4 in aggregating mesenchyme and simple epithelial bodies during metanephric development. sFRP-2 expression is absent in metanephric mesenchyme of kidneys mutant for Wnt-4 and is coinduced with Wnt-4 in isolated metanephric mesenchyme by cells expressing Wnt-4. The cysteine-rich domain of sFRP-2 binds to Wnt-4 as shown by coimmunoprecipitation experiments. Hence, sFRP-2 is a target of the Wnt-4 signaling pathway in the metanephric kidney and may modulate Wnt-4 signaling. sFRP-2 expression is highly dynamic and specific during other aspects of embryogenesis. sFRP-2 is expressed in subpopulations of ependymal cells in spinal cord and brain, in the developing eye, in limb bud mesenchyme, in the heart, and strongly in skeletogenic condensations of facial bones, suggesting widespread interaction with other members of the Wnt gene family during embryogenesis.

Animals↗

PubMed2001

A possible role for the WNT-1 pathway in oral carcinogenesis.

Reductions in cell-cell adhesion and stromal and vascular invasion are essential steps in the progression from localized malignancy to metastatic disease for all cancers. Proteins involved in intercellular adhesion, such as E-cadherin and catenin, probably play an important role in metastatic processes and cellular differentiation. While E-cadherin and beta-catenin expression has been extensively studied in many forms of human cancers, less is known about the role of the Wingless-Type-1 (WNT-1) pathway in human tumors. A large body of genetic and biochemical evidence has identified beta-catenin as a key downstream component of the WNT signaling pathway, and recent studies of colorectal tumors have shown a functional link among beta-catenin, adenomatous polyposis coli gene product (APC), and other components of the WNT-1 pathway. WNT-1 pathway signaling is thought to be mediated via interactions between beta-catenin and members of the LEF-1/TCF family of transcription factors. The WNT signal stabilizes beta-catenin protein and promotes its accumulation in the cytoplasm and nucleus. In the nucleus, beta-catenin associates with TCF to form a functional transcription factor which mediates the transactivation of target genes involved in the promotion of tumor progression, invasion, and metastasis, such as C-Myc, cyclin D1, c-jun, fra-1, and u-PAR. There is a strong correlation between the ability of the WNT-1 gene to induce beta-catenin accumulation and its transforming potential in vivo, suggesting that the WNT-1 gene activates an intracellular signaling pathway that can induce the morphological transformation of cells. For these reasons, data obtained from the study of the WNT-1 pathway could be important in our understanding of the mechanisms of epithelial tumors, in general, and probably also of oral squamous cell carcinoma, in particular.

Animals↗

PubMed2002

Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors.

Wnt-1 and Wnt-3a exhibit redundancy in neural crest development. We have found that they do not produce the same effects on PC12 cells, which were obtained from the adrenal medulla, a neural crest derivative. However, both Wnt-1 or Wnt-3a inhibit nerve growth factor (NGF)-induced neurite outgrowth. The inhibition is reversed by the protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, but it did not reverse Wnt-1-induced activation of the canonical Wnt pathway. The Wnt-1 inhibitory effect was not reversed by several other PKC inhibitors, by phorbol ester-induced down-regulation of PKC, or by pertussis toxin, which is known to inhibit another Wnt signaling pathway, the Wnt/Ca(2+) pathway. We suggest that bisindolylmaleimide-I acts by affecting either a pathway downstream from Lef-1/Tcf in the canonical pathway or a Wnt signaling pathway other than the canonical pathway. In either case, the bisindolylmaleimide-I sensitivity of this pathway should aid in its identification.

Animals↗

PubMed2006

Assessment of endostatin gene therapy for familial adenomatous polyposis-related desmoid tumors.

Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)-related desmoid tumors. Endostatin is a well-known antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease.

Adenomatous Polyposis Coli↗

PubMed2000

MITF: a stream flowing for pigment cells.

Microphthalmia-associated transcription factor (MITF) is a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLHZip) structure. Mutations of the MITF gene cause a variety of phenotypes, most notably in pigmented cells, in several species. In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome. Four isoforms have been cloned so far: MITF-M is the most abundant and is expressed in neural-crest-derived melanocytes; MITF-A is expressed in various cultured cells including retinal pigment epithelium (RPE) and enriched in RPE of embryonal and developing eyes; MITF-H are expressed in many types of cultured cells and in the heart tissue; MITF-C is expressed in many types of cultured cells, but not in melanocytes. Many growth factor signaling pathways have been implicated for regulation of MITF at both protein and promoter levels. Most notably, Steel factor/c-Kit signaling pathway was linked to phosphorylation of MITF at Ser73 and Ser409 through activation of MAP kinase and RSK-1, respectively. Phosphorylation of MITF is also conducted at Ser298 through GSK3beta, although the signaling pathway for this event still remains to be elucidated. IGF-1 and HGF/SF pathways may merge with the c-Kit signaling pathway. WNT and MSH signaling pathways regulate MITF positively at the promoter level. Endothelins may regulate MITF at the protein and promoter levels. MITF is involved in the differentiation, growth and survival of pigment cells, employing a number of signaling pathways.

Abnormalities, Multiple↗

PubMed2004

DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway.

Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the beta-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. TCF-binding elements have been found in the promoter regions of many TCF target genes and characterized by a highly conserved consensus sequence. Utilizing this consensus sequence, we performed an in silico screening for new TCF target genes. Through computational screening and subsequent experimental analysis, we identified a novel TCF target gene, DKK1, which has been shown to be a potent inhibitor of Wnt signaling. Our finding suggests the existence of a novel feedback loop in Wnt signaling.

Animals↗

PubMed2007

Gene expression studies of hepatitis virus-induced woodchuck hepatocellular carcinoma in correlation with human results.

The lack of good molecular markers for diagnosis as well as treatment assessment has rendered the hepatocellular carcinoma (HCC) a major challenge in health care. In this study, woodchucks were used as an animal model for hepatitis virus-induced HCC, and gene expression studies were performed using a human oligonucleotide microarray. An analysis approach combing supervised significant analysis of microarray (SAM), prediction analysis of microarray (PAM), and unsupervised hierarchical cluster methodologies statistically determined 211 upregulated and 78 downregulated genes between liver cancer and non-cancer liver tissues, and demonstrated > or = 93% accuracy in classifying the tissue samples. RT-PCR results confirmed the differential expression of selected sequenced woodchuck genes (SAT, IDH3B, SCD) in the microarray. Our study showed that differentially expressed genes were involved in transcription, RNA splicing, translation, cell cycle, metabolism, protein folding and degradation, apoptosis, immune response, metal binding, etc. Interestingly, some genes were involved with signaling pathways such as Ras/MAPK (MAPKAP1), Src-dependent pathways (CSK), hedgehog signaling pathway (HHIP), while Wnt signaling pathway may not be dominant in woodchuck HCC as shown by the downregulation of beta-catenin (TNNB1) and the upregulation of CXXC4 and CSNK2B. Numerous genes found in this study were also differentially expressed in human HCC and many other human cancers including breast, prostate and lung cancers, etc., serving as tumor suppressors, promoters, prognostic markers or chemotherapy targets. In conclusion, this study has demonstrated the robustness of the data analysis and the potential of using human microarrays on woodchuck samples. In particular, some of the differentially expressed genes in the woodchuck HCC can be further explored for possible molecular imaging targets or biological markers in human HCC.

Animals↗

PubMed2006

Gene expression profiling and analysis of signaling pathways involved in priming and differentiation of human neural stem cells.

Human neural stem cells have the ability to differentiate into all three major cell types in the CNS including neurons, astrocytes and oligodendrocytes. The multipotency of human neural stem cells shed a light on the possibility of using stem cells as a therapeutic tool for various neurological disorders including neurodegenerative diseases and neurotrauma that involve a loss of functional neurons. We have discovered previously a priming procedure to direct primarily cultured human neural stem cells to differentiate into almost pure neurons when grafted into adult CNS. However, the molecular mechanism underlying this phenomenon is still unknown. To unravel transcriptional changes of human neural stem cells upon priming, cDNA microarray was used to study temporal changes in human neural stem cell gene expression profile during priming and differentiation. As a result, transcriptional levels of 520 annotated genes were detected changed in at least at two time points during the priming process. In addition, transcription levels of more than 3000 hypothetical protein encoding genes and EST genes were modulated during the priming and differentiation processes of human neural stem cells. We further analyzed the named genes and grouped them into 14 functional categories. Of particular interest, key cell signal transduction pathways, including the G-protein-mediated signaling pathways (heterotrimeric and small monomeric GTPase pathways), the Wnt signaling pathway and the TGF-beta pathway, are modulated by the neural stem cell priming, suggesting important roles of these key signaling pathways in priming and differentiation of human neural stem cells.

Bone Morphogenetic Proteins↗

PubMed2000

WNT signalling molecules act in axis formation in the diploblastic metazoan Hydra.

Members of the Wnt/wingless family of secreted proteins act as short-range inducers and long-range organizers during axis formation, organogenesis and tumorigenesis in many developing tissues. Wnt signalling pathways are conserved in nematodes, insects and vertebrates. Despite its developmental significance, the evolutionary origin of Wnt signalling is unclear. Here we describe the molecular characterization of members of the Wnt signalling pathway--Wnt, Dishevelled, GSK3, beta-Catenin and Tcf/Lef--in Hydra, a member of the evolutionarily old metazoan phylum Cnidaria. Wnt and Tcf are expressed in the putative Hydra head organizer, the upper part of the hypostome. Wnt, beta-Catenin and Tcf are transcriptionally upregulated when head organizers are established early in bud formation and head regeneration. Wnt and Tcf expression domains also define head organizers created by de novo pattern formation in aggregates. Our results indicate that Wnt signalling may be involved in axis formation in Hydra and support the idea that it was central in the evolution of axial differentiation in early multicellular animals.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin.

BACKGROUND: Control of the nuclear localization of specific proteins is an important mechanism for regulating many signal transduction pathways. Upon activation of the Wnt signaling pathway, beta-catenin localizes into the nucleus and interacts with TCF/LEF-1 (T-cell factor/lymphocyte enhancer factor-1) transcription factors, triggering activation of downstream genes. The role of regulated nuclear localization in beta-catenin signaling is still unclear. Beta-catenin has no nuclear localization sequence (NLS). Although it has been reported that beta-catenin can piggyback into the nucleus by binding to TCF/LEF-1, there is evidence that its import is independent of TCF/LEF-1 in vivo. Therefore, the mechanism for beta-catenin nuclear localization remains to be established. RESULTS: We have analyzed beta-catenin nuclear import in an in vitro assay using permeabilized cells. Beta-catenin docks specifically onto the nuclear envelope in the absence of other cytosolic factors. Docking is not inhibited by an NLS peptide and does not require importins/karyopherins, the receptors for classical NLS substrates. Rather, docking is specifically competed by importin-beta/beta-karyopherin, indicating that beta-catenin and importin-beta/beta-karyopherin both interact with common nuclear pore components. Nuclear translocation of beta-catenin is energy dependent and is inhibited by nonhydrolyzable GTP analogs and by a dominant-negative mutant form of the Ran GTPase. Cytosol preparations contain inhibitory activities for beta-catenin import that are distinct from the competition by importin-beta/beta-karyopherin and may be involved in the physiological regulation of the pathway. CONCLUSIONS: Beta-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-beta/beta-karyopherin or other importin-beta-like import factors, such as transportin. These findings provide an explanation for how beta-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. The lack of beta-catenin import activity in the presence of normal cytosol suggests that its import may be regulated by upstream events in the Wnt signaling pathway.

Animals↗