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Catenin Signaling Pathway (catenin + signaling_pathway)
Selected AbstractsIng4 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] Novel genes involved in canonical Wnt/, -catenin signaling pathway in early Ciona intestinalis embryosDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2008Shuichi Wada We report here characterization of five genes for novel components of the canonical Wnt/, -catenin signaling pathway. These genes were identified in the ascidian Ciona intestinalis through a loss-of-function screening for genes required for embryogenesis with morpholinos, and four of them have counterparts in vertebrates. The five genes we studied are as follows: Ci-PGAP1, a Ciona orthologue of human PGAP1, which encodes GPI (glycosylphosphatidylinositol) inositol-deacylase, Ci-ZF278, a gene encoding a C2H2 zinc-finger protein, Ci-C10orf11, a Ciona orthologue of human C10orf11 that encodes a protein with leucine-rich repeats, Ci-Spatial/C4orf17, a single counterpart for two human genes Spatial and C4orf17, and Ci-FLJ10634, a Ciona orthologue of human FLJ10634 that encodes a member of the J-protein family. Knockdown of each of the genes mimicked , -catenin knockdown and resulted in suppression of the expression of , -catenin downstream genes (Ci-FoxD, Ci-Lhx3, Ci-Otx and Ci-Fgf9/16/20) and subsequent endoderm formation. For every gene, defects in knockdown embryos were rescued by overexpression of a constitutively active form, but not wild-type, of Ci- , -catenin. Dosage-sensitive interactions were found between Ci-,-catenin and each of the genes. These results suggest that these five genes act upstream of or parallel to Ci- , -catenin in the Wnt/, -catenin signaling pathway in early Ciona embryos. [source] Regulation of Wnt/,-catenin signaling by protein kinasesDEVELOPMENTAL DYNAMICS, Issue 1 2010Esther M. Verheyen Abstract The Wnt/,-catenin signaling pathway plays essential roles during development and adult tissue homeostasis. Inappropriate activation of the pathway can result in a variety of malignancies. Protein kinases have emerged as key regulators at multiple steps of the Wnt pathway. In this review, we present a synthesis covering the latest information on how Wnt signaling is regulated by diverse protein kinases. Developmental Dynamics 239:34,44, 2010. © 2009 Wiley-Liss, Inc. [source] Xenopus axin-related protein: A link between its centrosomal localization and function in the Wnt/,-catenin pathwayDEVELOPMENTAL DYNAMICS, Issue 1 2010Evguenia M. Alexandrova Abstract The Wnt/,-catenin signaling pathway regulates cell proliferation and cell fate determination in multiple systems. However, the subcellular localization of Wnt pathway components and the significance of this localization for the pathway regulation have not been extensively analyzed. Here we report that Xenopus Axin-related protein (XARP), a component of the ,-catenin destruction complex, is localized to the centrosome. This localization of XARP requires the presence of the DIX domain and an adjacent region. Since other components of the Wnt pathway have also been shown to associate with the centrosome, we tested a hypothesis that the ,-catenin destruction complex operates at the centrosome. However, XARP mutants with poor centrosomal localization revealed an enhanced rather than decreased ability to antagonize the Wnt/,-catenin pathway. Our data are consistent with the idea that the inactivation of XARP at the centrosome is an important regulatory point in Wnt signaling. Developmental Dynamics 239:261,270, 2010. © 2009 Wiley-Liss, Inc. [source] Wilms tumor genetics: Mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumorsGENES, CHROMOSOMES AND CANCER, Issue 6 2008E. Cristy Ruteshouser Wilms tumor is genetically heterogeneous, and until recently only one Wilms tumor gene was known, WT1 at 11p13. However, WT1 is altered in only ,20% of Wilms tumors. Recently a novel gene, WTX at Xq11.1, was reported to be mutated in Wilms tumors. No overlap between tumors with mutations in WTX and WT1 was noted, suggesting that WT1 and WTX mutations could account for the genetic basis of roughly half of Wilms tumors. To assess the frequency of WTX mutations and their relationship to WT1 mutations in a larger (n = 125) panel of Wilms tumors which had been thoroughly assessed for mutations in WT1, we conducted a complete mutational analysis of WTX that included sequencing of the entire coding region and quantitative PCR to identify deletions of the WTX gene. Twenty-three (18.4%) tumors carried a total of 24 WTX mutations, a lower WTX mutation frequency than that previously observed. Surprisingly, we observed an equivalent frequency of WTX mutations in tumors with mutations in either or both WT1 and CTNNB1 (20.0%) and tumors with no mutation in either WT1 or CTNNB1 (17.5%). WTX has been reported to play a role in the WNT/,-catenin signaling pathway, and, interestingly, WTX deletion/truncation mutations appeared to be rare in tumors carrying exon 3 mutations of CTNNB1, encoding ,-catenin. Our findings indicate that WT1 and WTX mutations occur with similar frequency, that they partially overlap in Wilms tumors, and that mutations in WT1, WTX, and CTNNB1 underlie the genetic basis of about one-third of Wilms tumors. © 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] Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/,-catenin signaling pathway,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009Macarena S. Arrázola Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of ,-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide. J. Cell. Physiol. 221: 658,667, 2009. © 2009 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] 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] The Cnidarian and the Canon: the role of Wnt/,-catenin signaling in the evolution of metazoan embryosBIOESSAYS, Issue 5 2004Alex Primus In a recent publication, Wikramanayake and colleagues have implicated the canonical Wnt/,-catenin signaling pathway as a mediator of axial polarity and germ-layer specification in embryos of the cnidarian Nematostella.1 In this anthozoan, ,-catenin is localized in nuclei of blastomeres in one region of the 16- to 32-cell embryo whose descendants subsequently form the entoderm of the embryo. They claim that the pattern of nuclear localization is significant for two reasons: (1) when nuclear localization of ,-catenin was inhibited, gastrulation does not occur, and (2) when localization of ,-catenin took place in all cells of the pregastrula embryo, the number of entodermal cells increases. Since the Wnt/,-catenin signaling pathway also plays a role in establishing axial polarity and specifying endoderm and mesoderm in a number of bilaterians,2,6 Wikramanayake et al. imply that this developmental mechanism is an evolutionary inheritance from a radially symmetrical ancestor. Some of the gaps in the current evidence, which must be filled to evaluate their interpretation, are discussed. BioEssays 26:474,478, 2004. © 2004 Wiley Periodicals, Inc. [source] Transforming properties of TC-1 in human breast cancer: Interaction with FGFR2 and ,-catenin signaling pathwaysINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Zeng-Quan Yang Abstract Breast cancer development is associated with gene amplification and over expression that is believed to have a causative role in oncogenesis. Previous studies have demonstrated that over expression of TC-1(C8orf4) mRNA occurs in ,50% of breast cancer cell lines and primary tumor specimens. Here, we show that TC-1 has transforming properties in human mammary epithelial (HME) cells and its expression is mechanistically linked to FGFR signaling cascades. In vitro experiments demonstrate that TC-1 over expression mediates both anchorage-independent and growth factor-independent proliferation of HME cells. TC-1 was down regulated by the FGFR inhibitor PD173074 in the breast cancer cell line SUM-52 that also has an FGFR2 gene amplification and over expression. Furthermore, forced expression of FGFR2 in HME cells increased the level of expression of endogenous TC-1 mRNA. TC-1 has been implicated as a modulator of Wnt/,-catenin signaling in 293 cells and in gastric cancer cells. However, while we did find increased expression of a subset of ,-catenin target genes in TC-1 over expressing cells, we did not find an association of TC-1 with global expression of ,-catenin target genes in our cells. Taken together, our data suggest that TC-1 over expression is transforming and may link with the FGFR pathway in a subset of breast cancer. © 2007 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] Regulation of Wnt/,-catenin pathway by cPLA2, and PPAR,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Chang Han Abstract Cytosolic phospholipase A2, (cPLA2,) is a rate-limiting key enzyme that releases arachidonic acid (AA) from membrane phospholipid for the production of biologically active lipid mediators including prostaglandins, leukotrienes and platelet-activating factor. cPLA2, is translocated to nuclear envelope in response to intracellular calcium increase and the enzyme is also present inside the cell nucleus; however, the biological function of cPLA2, in the nucleus remains unknown. Here we show a novel role of cPLA2, for activation of peroxisome proliferator-activated receptor-, (PPAR,) and ,-catenin in the nuclei. Overexpression of cPLA2, in human cholangiocarcinoma cells induced the binding of PPAR, to ,-catenin and increased their association with the TCF/LEF response element. These effects are inhibited by the cPLA2, siRNA and inhibitors as well as by siRNA knockdown of PPAR,. Overexpression of PPAR, or treatment with the selective PPAR, ligand, GW501516, also increased ,-catenin binding to TCF/LEF response element and increased its reporter activity. Addition of AA and GW501516 to nuclear extracts induced a comparable degree of ,-catenin binding to TCF/LEF response element. Furthermore, cPLA2, protein is present in the PPAR, and ,-catenin binding complex. Thus the close proximity between cPLA2, and PPAR, provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA2, becomes immediately available for PPAR, binding and subsequent ,-catenin activation. These results depict a novel interaction linking cPLA2,, PPAR, and Wnt/,-catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases. J. Cell. Biochem. 105: 534,545, 2008. © 2008 Wiley-Liss, Inc. [source] | |||||||||||||