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Catenin Signaling (catenin + signaling)
Terms modified by Catenin Signaling Selected AbstractsTargeted Gene Expression Analysis in Hemimegalencephaly: Activation of ,-Catenin SignalingBRAIN PATHOLOGY, Issue 3 2005Jia Yu MD Hemimegalencephaly (HMEG) is a developmental brain malformation characterized by unilateral hemispheric enlargement, cytoarchitectural abnormalities, and an association with epilepsy. To define the developmental pathogenesis of HMEG, the expression of 200 cell signaling, growth, angiogenic, and transcription factor genes was assayed in HMEG samples (n = 8) with targeted cDNA arrays. Differential expression of 31 mRNAs across the 4 gene families was identified in HMEG compared with control cortex. Increases in growth and transcription factor genes included JNK-1, cyclic AMP response element binding protein (CREB), and tuberin mRNAs and decreases included insulin-like growth factor-1 (IGF-1), transforming growth factor ,-3 (TGF-,3), and NFkB mRNAs. Increased expression of cyclin D1, c-myc, and WISP-1 mRNAs in HMEG suggested activation of the Wnt-1/,-catenin cascade. Western analysis demonstrated increased levels of non-phosphorylated ,-catenin, which transcriptionally activates cyclin D1 and c-myc genes, but reduced levels of Ser33/Ser37/Thr41 phospho-,-catenin, which is essential for ,-catenin-inactivation, in HMEG. Altered expression of 31 mRNAs from 4 gene families in human HMEG may lead to aberrant cell growth and hemispheric enlargement during brain development. Enhanced cyclin D1 and c-myc transcription likely reflects increased transcriptionally active ,-catenin due to decreased Ser33/Ser37/Thr41 phospho-,-catenin and suggests activation of the Wnt-1/,-catenin cascade in HMEG. [source] Organ patterning in the adult stage: The role of Wnt/,-catenin signaling in liver zonation and beyondDEVELOPMENTAL DYNAMICS, Issue 1 2010Rolf Gebhardt Abstract Wnt/,-catenin signaling has been found to play key roles in metabolic zonation of adult liver, regeneration, and hepatocellular carcinogenesis. In this review, recent progress in this field is summarized, in particular the rapidly growing knowledge about the various interactions of ,-catenin with many transcription factors involved in controlling metabolism. These interactions may provide the basis for understanding how the wide range of activities of Wnt/,-catenin signaling is differentially interpreted. Based on these results, a three-level mode for the molecular interpretation of ,-catenin activity gradients in liver is proposed favoring cell differentiation, metabolic zonation, and proliferation. While derangement of the combinatorial interplay of the various transcription factors with ,-catenin at the intermediary activity level may contribute to the development of metabolic diseases, extremely high activation of ,-catenin may eventually lead to initiation and progression of hepatocellular tumors. Developmental Dynamics 239:45,55, 2010. © 2009 Wiley-Liss, Inc. [source] Fzd3 and Fzd6 deficiency results in a severe midbrain morphogenesis defectDEVELOPMENTAL DYNAMICS, Issue 1 2010Sebastian Stuebner Abstract Wnt/,-catenin signaling controls the proper development of the mid-/hindbrain region (MHR) and of midbrain dopaminergic (mDA) neurons, but the Frizzled (Fzd) receptors transducing these signals are still unknown. Fzd3 is expressed throughout the mouse anterior neural tube, whereas Fzd6 is restricted to the MHR. We show that the MHR is properly established and mDA neurons develop normally in Fzd6,/, mutants, but the number of mDA neurons is initially reduced and recovers at later stages in Fzd3,/, embryos. Fzd3,/,; Fzd6,/, double mutants exhibit a severe midbrain morphogenesis defect consisting of collapsed brain ventricles, apparent thickening of the neuroepithelium, focal disruption of the ventricular basal lamina and protrusion of individual cells, and increased proliferation at later stages, despite a normal closure of the anterior neural tube and the rescue of the mDA defect in these embryos. Fzd3 and Fzd6 thus control proper midbrain morphogenesis by a yet unknown mechanism in the mouse. Developmental Dynamics 239:246,260, 2010. © 2009 Wiley-Liss, Inc. [source] Nmi (N-Myc interactor) inhibits Wnt/,-catenin signaling and retards tumor growthINTERNATIONAL JOURNAL OF CANCER, Issue 3 2009Rebecca A. Fillmore Abstract We found that the expression levels of N-Myc interactor (Nmi) were low in aggressive breast cancer cell lines when compared with less aggressive cell lines. However, the lower levels in the aggressive lines were inducible by interferon-, (IFN-,). Because Nmi has been reported to be a transcription cofactor that augments IFN-, induced transcription activity, we decided to test whether Nmi regulates expression of Dkk1, which is also inducible by IFN-,. We established stable clones constitutively expressing Nmi in MDA-MB-231 (breast) and MDA-MB-435 (melanoma) cell lines. Dkk1 was significantly up-regulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription cofactor of Wnt pathway, ,-catenin. Treatment of the Nmi expressors with blocking antibody to Dkk1 restored ,-catenin protein levels. c-Myc is a known downstream target of activated ,-catenin signaling. Treatment of Nmi expressors with the proteosome inhibitor MG132, resulted in elevated ,-catenin levels with concomitant elevation of c-Myc levels. Our functional studies showed that constitutive expression of Nmi reduced the ability of tumor cells for the invasion, anchorage independent growth and tumor growth in vivo. Collectively, the data suggest that overexpression of Nmi inhibits the Wnt/,-catenin signaling via up-regulation of Dkk1 and retards tumor growth. © 2009 UICC [source] Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2008Guojun Bu Abstract Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/,-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/,-catenin antagonist. In the present study, we demonstrated that activation of Wnt/,-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 overexpression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/,-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A-induced NF-kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases. © 2008 Wiley-Liss, Inc. [source] Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of ,-catenin signalingJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2010Lai Wang Abstract Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt/,-catenin signaling pathway. Insulin-like growth factor 1 (IGF-1) has been described as a stabilizer of ,-catenin, and thyroid hormone is a known stimulator of IGF-1 receptor expression. The purpose of this study was to test the hypothesis that IGF-1 signaling is involved in the interaction between the thyroid hormone and the Wnt/,-catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation. The results show that IGF-1 and the IGF- receptor (IGF1R) stimulate Wnt-4 expression and ,-catenin activation in growth plate chondrocytes. The positive effects of IGF-1/IGF1R on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1. T3 activates IGF-1/IGF1R signaling and IGF-1-dependent PI3K/Akt/GSK-3, signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy. T3 -mediated Wnt-4 expression, ,-catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K/Akt signaling inhibitors LY294002 and Akti1/2. These data indicate that the interactions between thyroid hormone and ,-catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF-1/IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. While chondrocyte proliferation may be triggered by the IGF-1/IGF1R-mediated PI3K/Akt/GSK3, pathway, cell hypertrophy is likely due to activation of Wnt/,-catenin signaling, which is at least in part initiated by IGF-1 signaling or the IGF-1-activated PI3K/Akt signaling pathway. © 2010 American Society for Bone and Mineral Research [source] Carboxypeptidase Z (CPZ) Links Thyroid Hormone and Wnt Signaling Pathways in Growth Plate Chondrocytes,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2009Lai Wang Abstract Carboxypeptidase Z (CPZ) removes carboxyl-terminal basic amino acid residues, particularly arginine residues, from proteins. CPZ contains a cysteine-rich domain (CRD) similar to the CRD found in the frizzled family of Wnt receptors. We have previously shown that thyroid hormone regulates terminal differentiation of growth plate chondrocytes through activation of Wnt-4 expression and Wnt/,-catenin signaling. The Wnt-4 protein contains a C-terminal arginine residue and binds to CPZ through the CRD. The objective of this study was to determine whether CPZ modulates Wnt/,-catenin signaling and terminal differentiation of growth plate chondrocytes. Our results show that CPZ and Wnt-4 mRNA are co-expressed throughout growth plate cartilage. In primary pellet cultures of rat growth plate chondrocytes, thyroid hormone increases both Wnt-4 and CPZ expression, as well as CPZ enzymatic activity. Knockdown of either Wnt-4 or CPZ mRNA levels using an RNA interference technique or blocking CPZ enzymatic activity with the carboxypeptidase inhibitor GEMSA reduces the thyroid hormone effect on both alkaline phosphatase activity and Col10a1 mRNA expression. Adenoviral overexpression of CPZ activates Wnt/,-catenin signaling and promotes the terminal differentiation of growth plate cells. Overexpression of CPZ in growth plate chondrocytes also removes the C-terminal arginine residue from a synthetic peptide consisting of the carboxyl-terminal 16 amino acids of the Wnt-4 protein. Removal of the C-terminal arginine residue of Wnt-4 by site-directed mutagenesis enhances the positive effect of Wnt-4 on terminal differentiation. These data indicate that thyroid hormone may regulate terminal differentiation of growth plate chondrocytes in part by modulating Wnt signaling pathways through the induction of CPZ and subsequent CPZ-enhanced activation of Wnt-4. [source] Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signalingJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2010Monica D. David Abstract Wnt factors regulate neural stem cell development and neuronal connectivity. Here we investigated whether Wnt-3a and Wnt-3, expressed in the developing spinal cord, regulate proliferation and the neuronal differentiation of spinal cord neural precursors (SCNP). Wnt-3a promoted a sustained increase of SCNP proliferation and decreased the expression of cyclin-dependent kinase inhibitors. In contrast, Wnt-3 transiently enhanced SCNP proliferation and increased neurogenesis through ,-catenin signaling. Furthermore, both Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through ,-catenin- and TCF4-dependent transcription. Glycogen synthase kinase-3, inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 factors signal through the canonical Wnt/,-catenin pathway to regulate different aspects of SCNP development. These findings may be of therapeutic interest for the treatment of neurodegenerative diseases and nerve injury. © 2010 Wiley-Liss, Inc. [source] Putative signaling action of amelogenin utilizes the Wnt/,-catenin pathwayJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2009M. Matsuzawa Background and Objective:, While it has long been known that amelogenin is essential for the proper development of enamel, its role has generally been seen as structural in nature. However, our new data implicate this protein in the regulation of cell signaling pathways in periodontal ligament cells and osteoblasts. In this article we report the successful purification of a recombinant mouse amelogenin protein and demonstrate that it has signaling activity in isolated mouse calvarial cells and human periodontal ligament cells. Material and Methods:, To determine the regulatory function of canonical Wnt signaling by amelogenin, we used TOPGAL transgenic mice. These mice express a ,-galactosidase transgene under the control of a LEF/TCF and ,-catenin-inducible promoter. To investigate in greater detail the molecular mechanisms involved in the ,-catenin signaling pathway, isolated osteoblasts and periodontal ligament cells were exposed to full-length recombinant mouse amelogenin and were evaluated for phenotypic changes and ,-catenin signaling using a TOPFLASH construct and the LacZ reporter gene. Results:, In these in vitro models, we showed that amelogenin can activate ,-catenin signaling. Conclusion:, Using the TOPGAL transgenic mouse we showed that amelogenin expression in vivo is localized mainly around the root, the periodontal ligament and the alveolar bone. [source] Upregulation of ,-Catenin Levels in Superior Frontal Cortex of Chronic AlcoholicsALCOHOLISM, Issue 6 2008Ali M. Al-Housseini Background:, Chronic and excessive alcohol misuse results in neuroadaptive changes in the brain. The complex nature of behavioral, psychological, emotional, and neuropathological characteristics associated with alcoholism is likely a reflection of the network of proteins that are affected by alcohol-induced gene expression patterns in specific brain regions. At the molecular level, however, knowledge remains limited regarding alterations in protein expression levels affected by chronic alcohol abuse. Thus, novel techniques that allow a comprehensive assessment of this complexity will enable the simultaneous assessment of changes across a group of proteins in the relevant neural circuitry. Methods:, A proteomics analysis was performed using antibody microarrays to determine differential protein levels in superior frontal cortices between chronic alcoholics and age- and gender-matched control subjects. Seventeen proteins related to the catenin signaling pathway were analyzed, including ,-, ,-, and ,-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1,, GSK-3,, PP2A-C,, and APC, as well as the nuclear complex partner of ,-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, G,1, G,1, and G,2, which are activity regulators of GSK-3,, were also analyzed. Results:, Both ,- and ,-catenin showed significantly increased levels, while ,-catenin did not change significantly, in chronic alcoholics. In addition, the level of the ,-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1,, and APC were also increased in chronic alcoholics, but the changes were not statistically significant. Conclusion:, Chronic and excessive alcohol consumption leads to an upregulation of ,- and ,-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by ,-catenin signaling. This study showed that the ,-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of ,- and ,-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance. [source] Prognostic significance of ,-catenin and topoisomerase II, in de novo acute myeloid leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2009Chih-Cheng Chen The Wnt/,-catenin signaling is important for controlling self-renewal of hematopoietic stem cells and its constitutive activation has recently been documented in a significant proportion of acute myeloid leukemia (AML) cases. Topoisomerase II, (Topo II,) is a marker of cell proliferation and a crucial target for anthracycline cytotoxicity, the mainstay of management employed in AML. We retrospectively investigated the prognostic roles of ,-catenin and topo II, in a cohort of 59 patients with newly diagnosed AML by immunohistochemistry. Aberrant ,-catenin expression was demonstrated in 13 patients (22%), and it was more likely to occur in those with unfavorable karyotypes. Advanced age and poor performance status adversely influenced the achievement of complete remission, while neither aberrant ,-catenin expression nor enhanced topo II, activity did. On multivariate survival analysis, four factors independently predicted a shortened overall survival: aberrant ,-catenin expression, high topo II, activity, poor-risk cytogenetics, and presence of at least one comorbidity factor. Our results suggest that both ,-catenin and topo II, independently predicted an adverse prognosis and might serve as new markers for risk stratification in AML patients. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt-1/,-Catenin Signaling PathwayTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 5 2008Xiaomei Li Abstract ING4, as a novel candidate tumor suppressor gene, has been implicated in several human malignances by tumor growth inhibition and apoptosis enhancement. The mechanism of ING4 remains largely unknown. The purpose of this study was to investigate the inhibitory tumor growth effects of ING4 on lung adenocarcinoma, and its mechanism, by ING4 cDNA transduction into A549 cells. Furthermore, the expression level of ING4 in lung adenocarcinoma tissues was examined. The expression of ING4 was markedly reduced in human lung adenocarcinoma tissues. Overexpression of ING4 can induce growth inhibition in A549 cells both in vitro and in vivo, and also induce up-regulation of p27, down-regulation of cyclinD1, SKP2, and Cox2, and inactivation of the Wnt-1/,-catenin pathway. Moreover, overexpression of ING4 can enhance the sensitivity of A549 cells to radiotherapy and chemotherapy. Thus, ING4 may play an inhibitory role on A549 cell proliferation and tumor growth in lung adenocarcinoma by up-regulation or down-regulation of cell proliferation-regulating proteins such as p27, cyclinD1, SKP2, and Cox2 by means of inactivation of Wnt-1/,-catenin signaling. Anat Rec, 291:593,600, 2008. © 2008 Wiley-Liss, Inc. [source] Enhancement of intervertebral disc cell senescence by WNT/,-catenin signaling,induced matrix metalloproteinase expressionARTHRITIS & RHEUMATISM, Issue 10 2010Akihiko Hiyama Objective To determine whether intervertebral disc (IVD) cells express ,-catenin and to assess the role of the WNT/,-catenin signaling pathway in cellular senescence and aggrecan synthesis. Methods The expression of ,-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription,polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/,-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated ,-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGF,)/bone morphogenetic protein (BMP) pathway,focused microarray analysis. Results We found that ,-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased ,-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/,-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/,-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGF, in NP cells. Conclusion The activation of WNT/,-catenin signaling promotes cellular senescence and may modulate MMP and TGF, signaling in NP cells. We hypothesize that the activation of WNT/,-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration. [source] Prostaglandin E2, Wnt, and BMP in gastric tumor mouse modelsCANCER SCIENCE, Issue 10 2009Hiroko Oshima The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori -associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE2. The COX-2/PGE2 pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/,-catenin signaling is found in 30,50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE2 pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE2, Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE2 induction, Wnt activation, BMP suppression, or a combination of these pathways. (Cancer Sci 2009; 100: 1779,1785) [source] Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodentsCANCER SCIENCE, Issue 6 2004Mami Takahashi Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the ,-catenin gene in its GSK-3, phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of ,-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of ,-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (INOS) and the inducible type of cyclooxyge-nase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of INOS is an early and important event occurring in step with ,-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of INOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E2 (PGE2) receptors may be altered in colon cancers. For example, the EP, and EP2 subtypes have been shown to be up-regulated and EP3 down-regulated in AOM-induced colon cancers in rats and mice. EP, and EP4 appear to be involved in ACF formation, while alteration in EP2 and EP3 is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/,-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man. [source] | |||||||||||||