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Catenin Activation (catenin + activation)
Selected AbstractsThyroid 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] Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genesTHE JOURNAL OF PATHOLOGY, Issue 2 2003Wilhelm Prange Abstract Beta-catenin integrates intracellular WNT signalling and the intercellular E-cadherin,catenin adhesion system. To date, little is known about the role of ,-catenin activation and nuclear accumulation in hepatocarcinogenesis. This study has analysed ,-catenin expression patterns in human dysplastic nodules (DNs), as well as in hepatocellular carcinomas (HCCs) in comparison with proliferation, expression of WNT-1 target genes, E-cadherin, and p53. One hundred and seventy HCCs and 25 DNs were categorized according to established criteria and analysed for the expression pattern of ,-catenin. Analysis of the proliferative activity and expression of E-cadherin, cyclin D1, MMP-7, c-myc, and p53 was performed on a representative subgroup of cases. All DNs lacked nuclear ,-catenin, while 36% of all HCCs were positive, with the number of nuclear stained cells ranging from less than 1% to more than 90%. Increasing nuclear accumulation of ,-catenin correlated with reduced membranous E-cadherin expression and nuclear p53 but not with proliferation. Cyclin D1, MMP-7, and c-myc expression was detected in 54%, 26%, and 65% of HCCs, respectively, but did not correlate with nuclear ,-catenin, proliferation, or grading. Sequence analysis of the ,-catenin gene revealed no detectable mutations in DNs, but mutations in the GSK-3, binding site were present in 14.3% of the HCCs. In conclusion, this study has demonstrated that nuclear accumulation of ,-catenin is a frequent progression event in human hepatocarcinogenesis which correlates with nuclear p53 accumulation and loss of membranous E-cadherin, but not with the expression pattern of established WNT-1 target genes. It is hypothesized that the role of ,-catenin in human HCC differs significantly from its established function in colon carcinogenesis. Copyright © 2003 John Wiley & Sons, Ltd. [source] Glycogen synthase kinase-3, does not correlate with the expression and activity of ,-catenin in gastric cancerAPMIS, Issue 10 2010YU-JIN CHO Cho Y-J, Yoon J, Ko Y-S, Kim S-Y, Cho S-J, Kim W-H, Park J-W, Youn H-D, Kim J-H, Lee B-L. Glycogen synthase kinase-3, does not correlate with the expression and activity of ,-catenin in gastric cancer. APMIS 2010; 118: 782,90. The regulation of ,-catenin activation by glycogen synthase kinase-3, (GSK-3,) in cancer has been shown to be cell type-specific. This study was performed to investigate the relationship between activated GSK-3, (phosphorylated at Tyr216) and ,-catenin in gastric cancer. Immunohistochemical tissue array analysis of 278 human gastric carcinoma specimens showed positive immunoreactivity for activated GSK-3, in 44% of the samples, whereas membranous ,-catenin and nuclear ,-catenin were observed in 19% and 20% of the samples, respectively. However, GSK-3, activation was not correlated with the expression of either membranous ,-catenin or nuclear ,-catenin. Moreover, SNU gastric cancer cell lines over-expressing kinase dead GSK-3, and the same cells treated with a GSK-3, inhibitor showed that GSK-3, inhibition did not alter either the protein expression or transcriptional activity of ,-catenin. In addition, GSK-3, activation was positively correlated with the expressions of anti-adenomatous polyposis coli (p = 0.002), p16 (p < 0.001), p21 (p < 0.001), p27 (p = 0.001), and p53 (p = 0.013). On the other hand, the nuclear expression of ,-catenin was positively correlated with those of Bcl-2 (p = 0.025) and cyclin D1 (p = 0.043), but these expressions were not correlated with GSK-3, activation. Thus, the GSK-3, pathway seems to function in gastric cancer cells without involving the ,-catenin pathway. [source] | ||||||||||