|
| ||
|
|
||
Catenin Accumulation (catenin + accumulation)
Selected AbstractsGlycogen synthase kinase 3, and ,-catenin pathway is involved in toll-like receptor 4-mediated NADPH oxidase 1 expression in macrophagesFEBS JOURNAL, Issue 13 2010Jin-Sik Kim Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood. We found that LPS causes ,-catenin accumulation by glycogen synthase kinase 3, (GSK3,) inactivation, and that ,-catenin accumulation increases Nox1 expression. LPS induced Nox1 mRNA expression and reactive oxygen species generation in Raw264.7 cells. Using bone marrow-derived macrophages from toll-like receptor 4 mutant mice, we also tested whether LPS-induced Nox1 expression is toll-like receptor 4 dependent. LPS caused GSK3, phosphorylation, induced ,-catenin accumulation and increased nuclear translocation. The GSK3, inhibitor LiCl potentiated LPS-induced Nox1 expression in accordance with ,-catenin accumulation and nuclear translocation. Conversely, ectopic expression of a constitutively active GSK3, mutant severely attenuated Nox1 expression. These findings identify a novel regulatory pathway controlling Nox1 expression by LPS-stimulated macrophages. [source] Cytoplasmic ,-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomasHISTOPATHOLOGY, Issue 1 2010Michael G A Norwood Norwood M G A, Bailey N, Nanji M, Gillies R S, Nicholson A, Ubhi S, Darnton J J, Steyn R S, Womack C, Hughes A, Hemingway D, Harrison R, Waters R & Jankowski J A (2010) Histopathology,57, 101,111 Cytoplasmic ,-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas Aims:, ,-Catenin is an important molecule in cancer biology. Membranous ,-catenin enhances cellular differentiation and inhibits invasion by its action on E-cadherin. The aim was to ascertain whether the cellular expression of these molecules in colorectal and oesophageal cancer specimens is associated with survival in patients with gastrointestinal cancer. Methods and results:, Tumour samples from 149 patients undergoing resection for colorectal adenocarcinoma and 147 patients undergoing resection for oesophageal adenocarcinoma were retrospectively analysed using immunohistochemical techniques to assess ,-catenin expression. Increasing ,-catenin expression in the cytoplasm was associated with improved survival for colorectal cancer cases on both univariate (P = 0.003) and multivariate (P = 0.01) analysis. In addition, increased expression in the most recent cohort of oesophageal adenocarcinoma patients was associated with improved TNM staging (P = 0.007). Membrane expression was weakly associated with survival in colorectal cancer on univariate analysis (P = 0.09), but not on multivariate analysis (P = 0.21). Complete absence of ,-catenin expression at all three sites was associated with reduced 5-year survival in colorectal cancer. Conclusions:, This is one of the largest prognostic studies of ,-catenin in gastrointestinal adenocarcinoma. It shows that low levels of cytoplasmic ,-catenin expression are associated with reduced survival in patients with colorectal cancer as well as worse TNM staging in oesophageal adenocarcinoma (a recognized surrogate end-point for survival). We believe this is the first time that this has been reported. This finding should be tested prospectively in oncological trials to validate whether the presence of cytoplasmic ,-catenin could be used as a prognostic marker for less aggressive disease. [source] Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signalingJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Christopher M. Amantea Abstract Osteoporosis and its complications cause morbidity and mortality in the aging population, and result from increased bone resorption by osteoclasts in parallel with decreased bone formation by osteoblasts. A widely accepted strategy for improving bone health is targeting osteoprogenitor cells in order to stimulate their osteogenic differentiation and bone forming properties through the use of osteoinductive/anabolic factors. We previously reported that specific naturally occurring oxysterols have potent osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells. In the present report, we further demonstrate the molecular mechanism(s) by which oxysterols induce osteogenesis. In addition to activating the hedgehog signaling pathway, oxysterol-induced osteogenic differentiation is mediated through a Wnt signaling-related, Dkk-1-inhibitable mechanism. Bone marrow stromal cells (MSC) treated with oxysterols demonstrated increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes. These oxysterol effects, which occurred in the absence of ,-catenin accumulation or TCF/Lef activation, were inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk-1. Furthermore, the inhibitors of PI3-Kinase signaling, LY 294002 and wortmanin, inhibited oxysterol-induced osteogenic differentiation and induction of Wnt signaling target genes. Finally, activators of canonical Wnt signaling, Wnt3a and Wnt1, inhibited spontaneous, oxysterol-, and Shh-induced osteogenic differentiation of bone marrow stromal cells, suggesting the involvement of a non-canonical Wnt pathway in pro-osteogenic differentiation events. Osteogenic oxysterols are, therefore, important small molecule modulators of critical signaling pathways in pluripotent mesenchymal cells that regulate numerous developmental and post-developmental processes. J. Cell. Biochem. 105: 424,436, 2008. © 2008 Wiley-Liss, Inc. [source] Association between activation of atypical NF-,B1 p105 signaling pathway and nuclear ,-catenin accumulation in colorectal carcinomaMOLECULAR CARCINOGENESIS, Issue 2 2010Johannes C. Lauscher Abstract Recent studies have demonstrated that increased expression of coding region determinant-binding protein (CRD-BP) in response to ,-catenin signaling leads to the stabilization of ,-TrCP1, a substrate-specific component of SCF E3 ubiquitin ligase complex, resulting in an accelerated degradation of I,B, and activation of canonical nuclear factor-,B (NF-,B) pathway. Here, we show that the noncanonical NF-,B1 p105 pathway is constitutively activated in colorectal carcinoma specimens, being particularly associated with ,-catenin-mediated increased expression of CRD-BP and ,-TrCP1. In the carcinoma tissues exhibiting high levels of nuclear ,-catenin the phospho-p105 levels were increased and total p105 amounts were decreased in comparison to that of normal tissue indicating an activation of this NF-,B pathway. Knockdown of CRD-BP in colorectal cancer cell line SW620 resulted in significantly higher basal levels of both NF-,B inhibitory proteins, p105 and I,B,. Furthermore decreased NF-,B binding activity was observed in CRD-BP siRNA-transfected SW620 cells as compared with those transfected with control siRNA. Altogether, our findings suggest that activation of NF-,B1 p105 signaling in colorectal carcinoma might be attributed to ,-catenin-mediated induction of CRD-BP and ,-TrCP1. © 2009 Wiley-Liss, Inc. [source] ,-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breastTHE JOURNAL OF PATHOLOGY, Issue 5 2003Elinor J Sawyer Abstract The aim of this study was to assess the expression of IGF-I and IGF-II in phyllodes tumours and fibroadenomas and to see if there is any correlation between nuclear ,-catenin expression and IGF-I and IGF-II expression in these tumours. In a previous study, it has been shown that Wnt signalling is important in the pathogenesis of phyllodes tumours of the breast. Epithelial Wnt5a overexpression and stromal Wnt2 overexpression were associated with abnormal, nuclear localization of ,-catenin in the stromal cells of these tumours. However, not all tumours with ,-catenin accumulation showed Wnt overexpression. One other possible cause of ,-catenin accumulation is overexpression of insulin-like growth factors (IGFs), as both IGF-I and IGF-II have been shown to stabilize ,-catenin. In this study, 30 fibroadenomas of the breast were assessed for ,-catenin expression using immunohistochemistry and the results were compared with previous data from 119 phyllodes tumours. In situ hybridization was used to assess IGF-I and IGF-II expression in 23 phyllodes tumours and 16 fibroadenomas. Nineteen phyllodes tumours (83%) showed widespread overexpression of IGF-II and 5/23 (22%) showed widespread overexpression of IGF-I. IGF-I expression correlated with nuclear ,-catenin staining in phyllodes tumours. Malignant phyllodes tumours showed no or little IGF-I expression. There was a degree of nuclear ,-catenin expression in the stroma (weak in 33%, moderate in 27%, and strong in 40%) in all fibroadenomas and nuclear ,-catenin staining correlated with IGF-I overexpression. Extensive IGF-II overexpression was also found in the majority of fibroadenomas (12/16). These results support the hypothesis that IGF-I and IGF-II overexpression may be important in the pathogenesis of fibroepithelial neoplasms of the breast and that IGF-I overexpression is likely to be contributing to the nuclear ,-catenin localization observed in the tumours. Copyright © 2003 John Wiley & Sons, Ltd. [source] Target Gene Activation of the Wnt Signaling Pathway in Nuclear ,-Catenin Accumulating Cells of Adamantinomatous CraniopharyngiomasBRAIN PATHOLOGY, Issue 3 2009Annett Hölsken Abstract Activating ,-catenin (CTNNB1) mutations can be identified in the majority of adamantinomatous craniopharyngiomas (adaCP), suggesting an aberrant Wnt signaling pathway in this histopathologically peculiar tumor entity. However, there is no proven evidence that nuclear translocation of ,-catenin is associated with CTNNB1 mutations and target gene activation. We performed a laser-microdissection-based study comparing ,-catenin accumulating vs. non-accumulating tumor cells. Mutational analysis and gene expression profiling using real-time polymerase chain reaction were conducted in adamantinomatous and papillary tumor specimens. Target gene activation, that is, over-expression of Axin2 could be detected in adaCP, especially in tumor cells with nuclear ,-catenin accumulation. In addition, increased expression of BMP4 was identified in the accumulating cell population, which supports the hypothesis of an oral ectodermal origin. Interestingly, accumulating and non-accumulating tumor cell populations carried CTNNB1 mutations within exon 3. We extended the analysis, therefore, towards genetic regions encoding for membrane linkage and active/passive nuclear transport mechanisms (exon 4 and exon 8,13), but could not detect any alteration. This is the first report demonstrating an association between nuclear ,-catenin accumulation and target gene activation in adaCP. The results confirm the Wnt signaling pathway as molecular basis of the distinct and challenging clinical and morphological phenotype of adaCP. [source] Nuclear ,-catenin in basal cell carcinoma correlates with increased proliferationBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2004G. Saldanha Summary Background Virtually all BCCs have deregulation of the Hedgehog (Hh) signalling pathway and a proportion show nuclear ,-catenin accumulation. The latter is thought to be due to Hh pathway-directed Wnt expression but this has not been tested. An alternative cause of nuclear ,-catenin accumulation is gene mutation, which stabilizes the protein. Theoretically, reduced E-cadherin expression could also be important because it can sequester ,-catenin at the cell membrane. In turn, nuclear ,-catenin can increase expression of MYC and cyclin D1, thus potentially altering proliferation. Objectives To assess whether nuclear ,-catenin occurs in BCC, and to look at potential causes and consequences. Methods Nuclear ,-catenin was assessed by immunohistochemistry, and its causes by analysis of E-cadherin expression, ,-catenin exon 3 mutation and WNT5A expression. Its consequences were assessed by analysing proliferation. Results We found nuclear ,-catenin in 20 of 86 paraffin-embedded sections of BCCs using immunohistochemistry. BCCs showed increased WNT5A relative to the surrounding skin. No mutations in exon 3 of the ,-catenin gene were found in 10 cases. There was no association between ,-catenin localization and E-cadherin expression. Tumours with nuclear ,-catenin had significantly higher proliferation (P < 0·01). Conclusions The absence of ,-catenin gene mutations indicate that the Hh pathway-directed Wnt signalling remains the most likely cause of nuclear ,-catenin accumulation in BCC. Additionally, the correlation with increased proliferation is the first evidence that nuclear ,-catenin may have a biological effect. However, a causal link between Hh pathway deregulation, Wnt ligand overexpression, nuclear ,-catenin accumulation and increased proliferation remains to be confirmed. [source] The intratumoral distribution of nuclear ,-catenin is a prognostic marker in colon cancerCANCER, Issue 10 2009David Horst MD Abstract BACKGROUND: Most colon cancers harbor mutations of APC or ,-catenin, both of which may lead to nuclear ,-catenin accumulation in the tumor cells and constitutively activated expression of its target genes. In many colon cancers, however, nuclear ,-catenin accumulation is heterogeneous throughout the tumor and often confined to the tumor margin. Herein, the authors investigated whether the intratumoral distribution of nuclear ,-catenin can serve as a prognostic marker for survival and tumor progression of stage IIA colon cancer patients. METHODS: In total, 142 patients with primarily resected, moderately differentiated stage IIA colon cancer were included in this study. The patterning of nuclear ,-catenin expression was evaluated on immunohistochemically stained whole tissue sections of the tumors and was correlated with cancer-specific survival and disease-free survival using univariate and multivariate statistical analyses. RESULTS: Four distinct patterns of nuclear ,-catenin expression were identified, and 2 main categories comprising tumors with or without intratumoral regulation of nuclear ,-catenin were distinguished. Moreover, the results demonstrated that the patterning, and especially the regulation or absence of regulation of nuclear ,-catenin expression, was a strong predictive marker of patient survival and tumor progression. CONCLUSIONS: The current results indicated that the distribution of nuclear ,-catenin expression can be used as a good prognostic marker in patients with stage IIA colon cancer. Thus, the evaluation of nuclear ,-catenin may help to identify patients who will have a shorter than average survival and patients with a greater risk of disease progression who may be considered for adjuvant therapeutic modalities and intensified clinical aftercare in the future. Cancer 2009. © 2009 American Cancer Society. [source] | ||||||||||||||||||||||