Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss or reduced expression of E-cadherin has been shown to be associated with poor survival in patients with bladder cancer. In numerous cases, loss of E-cadherin expression in bladder tumors has been accompanied by continued association of catenins with the membrane, suggestive of the expression of an alternative cadherin member. In this study we examined 75 bladder tumors using immunohistochemistry for the expression of E-, P-cadherin, and alpha-, beta-, and gamma-catenins. As reported previously, loss or reduced E-cadherin expression is a frequent event in late stage bladder cancer, accompanied by less frequent alterations associated with different catenin family members. Analysis of 51 tumors for expression of E-, P-, and N-cadherin showed P-cadherin localized to the basal cell layers of normal urothelium, with retention of expression in the majority of tumors. In low-grade tumors P-cadherin was found localized to an expanded basal cell compartment, contrasting with the more extensive staining observed in late stage tumors. Membranous P-cadherin staining was often found in the absence of E-cadherin staining. N-cadherin is not expressed in normal bladder mucosa, but detection of this cadherin member was recorded in 39% (20/51) of bladder tumors. Unlike P-cadherin, membranous N-cadherin was detected in focal regions within tumors, representing novel expression in urothelial neoplastic progression. Although focal N-cadherin staining was observed in 3 noninvasive lesions, the majority of tumors expressing N-cadherin were invasive (17/20). Coexpression of E-, P-, and N-cadherin was recorded in 5 grade 2 bladder tumors. Expression of P-cadherin is maintained throughout bladder tumorigenesis, accompanied by aberrant expression of N-cadherin. Clearly, neither P- nor N-cadherin act in an invasive-suppressor mode in bladder cancer, but whether they have a primary role to play in urothelial neoplastic progression has yet to be established.
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PMID:Expression of classic cadherins type I in urothelial neoplastic progression. 1117 90

Beta-catenin is a component of the E-cadherin-catenin cell adhesion complex. It plays also a role in intracellular signaling and can function as an oncogene when it binds to the T-cell factor 4 (Tcf4)-binding site in the promoter region of cyclin D1 and transactivates genes after translocation to the nucleus. We evaluated the immunohistochemical expression pattern of beta-catenin in relationship with cyclin D1 overexpression, tumor grade, clinicopathologic parameters and patients' survival in 43 ductal adenocarcinomas of the pancreas and 5 normal pancreatic tissues. We were able to show that, both reduced membranous beta-catenin expression (25 of 43, 58.1%) and accumulation of beta-catenin in the cytoplasm (28 of 43, 65.1%) correlated significantly with cyclin D1 overexpression (both p < 0.0005). Furthermore, we could show a clear correlation between reduced membranous expression and ectopic cytoplasmic expression of beta-catenin (p < 0.0005). Among patients with carcinomas showing no cytoplasmic expression, the 1-year survival was 86.6% whereas among patients with carcinomas showing cytoplasmic expression only 35.7% survived 1 year (p < 0.01). Co-precipitation experiments revealed reduced beta-catenin bound to the E-cadherin-catenin complex in pancreatic tumor tissues compared with normal pancreatic tissues. These results suggest that beta-catenin may be involved in the tumorigenesis of pancreatic cancer and exhibited its effects mainly by the transactivation of cyclin D1.
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PMID:Reduced membranous and ectopic cytoplasmic expression of beta -catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer. 1130 54

It has been well-known that the cadherin-catenin complexes bind with intracellular skeleton actin, which result in stabilization of cellular structure and tissue organization. Therefore, the cadherin-catenin family has been considered prerequisite for normal cell function and the preservation of tissue integrity. In human malignancies especially colon cancers, dysfunction and/or decrease of expression of these proteins have been proposed to prevent differentiation of tumors and to increase invasiveness and poor prognosis. However, recent studies also revealed that a member of this superfamily, beta-catenin, may play an important role in Wnt/wingless intracellular signaling pathway. Decreased expression of this protein or somatic mutation of the beta-catenin gene has been also reported in human carcinomas including various endocrine tumors. Mutant beta-catenin is associated with abnormal nuclear accumulation in tumor cells and subsequently to activate other transcription factors such as Tcf/Lef. This activation eventually results in which upregulation of mRNA and protein levels of various cell growth mediators in these endocrine tumors. Therefore, dysfunction of the cadherin-catenin system is considered to be closely correlated with tumorigenesis and development in human endocrine tumors.
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PMID:The cadherin-catenin superfamily in endocrine tumors. 1147 63

Transforming growth factor beta1 (TGF-beta1) acts as a tumor suppressor at early stages of carcinogenesis, however, it has also been suggested to promote tumor progression at late stages. To determine at which stage and by what mechanisms this functional switch occurs, we have generated gene-switch-TGF-beta1 mice in which TGF-beta1 transgene expression can be induced in skin tumors at specific stages. These mice were exposed to a chemical carcinogenesis protocol, which allows tumorigenesis to develop in progressive stages from benign papillomas to malignant carcinomas. Remarkably, TGF-beta1 transgene induction in papillomas rapidly induced metastasis. This function is in sharp contrast to its tumor suppressive effect when TGF-beta1 transgene expression was induced early in the protocol. Transgenic papillomas exhibited down-regulation of TGF-beta receptors and their signal transducer, the Smads, and loss of the invasion suppressor E-cadherin/catenin complex in the cell membrane. These molecules were lost only in malignant carcinomas in control mice at a much later stage. Furthermore, transgenic papillomas exhibited elevated expression of matrix metalloproteinases and increased angiogenesis. Our study suggests that TGF-beta1 overexpression may directly induce tumor metastasis by initiating events necessary for invasion. Down-regulation of TGF-beta signaling components in tumor epithelia selectively abolishes growth inhibition, thus, switching the role of TGF-beta1 to a metastasis promoter.
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PMID:Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis. 1160 77

B -Catenin is closely associated with carcinoma invasion/metastasis and poor survival. Recent studies have demonstrated that abnormal expression of B -catenin, especially its nuclear accumulation, also plays an important role in wingless/Wnt signaling pathway. In this study, we evaluated immunohistochemically the nuclear localization of B -catenin in a total of 93 human-endocrine-related tumors including 1 medullary carcinoma (thyroid gland), 12 parathyroid tumors, 22 carcinoid tumors (digestive tract and liver), 7 islet cell tumors, 26 adrenocortical tumors, 13 neuroblastoma (adrenal gland), and 12 pheochromocytoma (adrenal gland), and also studied genetic alterations of the B -catenin gene. Nuclear accumulation of B -catenin was frequently detected in 8 of 22 (36%) carcinoid tumors and 2 of 7 (29%) islet cell tumors. No genetic alteration in exon 3 of the B -catenin gene encoding serine/threonine rich domain, which was phosphorylated by GSK-3 B, was detected in any groups of the endocrine tumors. However, nuclear accumulation of B -catenin in carcinoid tumors was significantly correlated with the proliferative marker Ki-67 (MIB-1) labeling index (p <0.001). Our findings suggest that nuclear transfer and accumulation of the B -catenin may contribute in the tumorigenesis of carcinoid tumor as an oncoprotein.
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PMID:Nuclear Accumulation of B-Catenin in Human Endocrine Tumors: Association with Ki-67 (MIB-1) Proliferative Activity. 1211 96

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
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PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

To clarify the roles of Wnt pathway in medulloblastoma oncogenesis, immunohistochemical staining of beta-catenin and Wnt-1 and genomic analyses of CTNNB1 (beta-catenin) and AXIN1 (axin 1) were examined in 23 sporadic cases. Accumulation of beta-catenin in tumor cells was immunohistochemically proven in 5 cases; 2 cases showed positive immunoreactivity for Wnt-1 and another 2 showed mutation of either CTNNB1 or AXIN1. AXIN1 mutation was in exon 3, corresponding to GSK-3beta binding site and CTNNB1 mutation was in exon 3, corresponding to its phosphorylation site. Disruption of these proteins could result in upregulation of the Wnt signaling and accumulation of beta-catenin, followed by cell proliferation and medulloblastoma oncogenesis.
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PMID:Role of Wnt pathway in medulloblastoma oncogenesis. 1220 99

The E-cadherin protein mediates Ca(2+)-dependent interepithelial adhesion. Association of E-cadherin with the catenin family of proteins is critical for the maintenance of a functional adhesive complex. We have identified a novel truncated E-cadherin species of 100-kDa (E-cad(100)) in prostate and mammary epithelial cells. E-cad(100) was generated by treatment of cells with ionomycin or TPA. Cell-permeable calpain inhibitors prevented E-cad(100) induction by ionomycin. Immunoblotting for spectrin and mu-calpain confirmed calpain activation in response to ionomycin treatment. Both the mu- and m-isoforms of calpain efficiently generated E-cad(100) in vitro. The E-cad(100) fragment was unable to bind to beta-catenin, gamma-catenin, and p120, suggesting that this cleavage event would disrupt the E-cadherin adhesion complex. Mutational analysis localized the calpain cleavage site to the cytosolic domain upstream of the beta- and gamma-catenin binding motifs of E-cadherin. Because E-cadherin is inactivated in many adenocarcinomas we hypothesized that calpain may play a role in prostate tumorigenesis. A prostate cDNA microarray data base was analyzed for calpain expression in which it was found that m-calpain was up-regulated in localized prostate cancer, and to an even higher degree in metastatic prostate cancer compared with normal prostate tissue. Furthermore, we examined the cleavage of E-cadherin in prostate cancer specimens and found that E-cad(100) accumulated in both localized and metastatic prostate tumors, supporting the cDNA microarray data. These findings demonstrate a novel mechanism by which E-cadherin is functionally inactivated through calpain-mediated proteolysis and suggests that E-cadherin is targeted by calpain during the tumorigenic progression of prostate cancer.
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PMID:The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells. 1239 69

The cadherin-catenin complex regulates cellular adhesion and motility, and genetic alterations in these molecules play a critical role in multistage tumorigenesis. In this study, the expression of three major type I classic cadherins E-, N-, and P-cadherin and their undercoat proteins alpha-, beta-, and gamma-catenin, and pp120 was investigated in 127 pituitary adenomas and 10 normal adenohypophyseal glands using an immunohistochemical technique with highly specific monoclonal antibodies. In normal pituitary glands, E-cadherin, catenins, and pp120 were strongly expressed on almost all hormone-producing cell-cell boundaries, N-cadherin was weakly immunoreactive on a few cell-cell boundaries, and P-cadherin was negative. In pituitary adenomas, a correlation was not identified among expression of E-cadherin, catenins, or pp120 with patient age, sex, hormone level, tumor size, and/or invasiveness, respectively. Expression of E-cadherin, catenins, and pp120 was significantly reduced in 24 growth hormone (GH) cell adenomas with prominent fibrous bodies compared with the other subtypes of pituitary adenomas and normal pituitary glands (p < 0.0001, respectively). Methylation-specific polymerase chain reaction analysis revealed that the E-cadherin gene promoter region was methylated in 6 of 16 (37.5%) GH cell adenomas with prominent fibrous bodies examined, 2 of which displayed total methylation, but not in 10 GH cell adenomas without fibrous bodies. No mutation of exon 3 of the beta-catenin gene was found in 16 GH cell adenomas with prominent fibrous bodies or in 10 other subtypes of pituitary adenomas that showed unremarkable intracellular presence of beta-catenin protein. In conclusion, the decreased expression of the E-cadherin catenin complex and methylation of the E-cadherin gene promoter region only in GH cell adenomas with prominent fibrous bodies may be an event associated with the formation of fibrous bodies.
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PMID:Downregulation of E-cadherin and its undercoat proteins in pituitary growth hormone cell adenomas with prominent fibrous bodies. 1266 52

Cells are held together either by direct cell-cell contact or adhesion to extra-cellular matrix. Cell-cell adhesion in epithelial cell sheets consists of junctions, i.e. tight-, adherens- and gap-junctions. The adherens junctions, which are build up by the cadherin/catenin complex, are the main topic of this review, especially the aspect of its role in ovarian tumor biology. The ovarian surface epithelium is the origin for approximately 90% of the malignant ovarian tumors. The tumors arise from the inclusion cysts, localized in the ovarian stroma and grow solid, cystic or in mixed formations. Intra-abdominal spread of the ovarian cancer is common and this is a process that theoretically could be closely connected with impaired cell-cell adhesion. However, as we stand today, descriptive and functional studies on the cadherin-catenin complex and its cell signaling role in ovarian tumorigenesis reveals data that suggests a conversion of the mesothelial-like cells of the ovarian surface to a more epithelial phenotype with normal cell-cell adhesion prior to tumor differentiation. In later stages, invasive ovarian tumors still strongly express several cadherins, which are contrary to many other tumors, i.e. prostate and thyroid adenocarcinomas.
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PMID:Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. 1277 Jul 36


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