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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoplasmic beta-catenin protein is implicated in signal transduction and associates with both the cell-cell adhesion protein E-cadherin and the tumor suppressor gene product APC. We determined the primary structure of the human beta-catenin gene (CTNNB1) by analysis of cDNA and genomic clones. The size of the complete gene was determined to be 23.2 kb. Restriction mapping and partial sequence analysis revealed 16 exons. All splice donor and acceptor sites were conformable to the GT/AG rule. The exon size ranged from 61 to 790 bp. Half of the introns were smaller than 550 bp, with the smallest being 84 bp and the longest being 6700 bp. The intron-exon boundaries did not coincide either with conserved sites in the 12 armadillo repeat sequences of beta-catenin or with intron-exon boundaries in the armadillo gene of Drosophila. A major site for transcription initiation was identified as an A residue 214 nucleotides upstream of the ATG initiation codon. The resulting transcript is 3362 nucleotides long. Compared to the previously published mRNA sequence, additional residues were identified, 16 at the 5' end and 766 at the 3' end of the mRNA. An alternative splice acceptor site within exon 16 reduced the 3' UTR sequence by 159 bp. Polymerase chain reaction on cDNA from 14 human cell lines demonstrated the general occurrence of both splice variants. The 5'-flanking region is highly GC-rich and lacks a CCAAT box, but contains a TATA box and potential binding sites for several transcription factors, such as NF kappa B, SP1, AP2, and EGR1. Both a 437-bp fragment and a 6-kb fragment, containing about 4.7 kb of the 5'-flanking region in addition to the noncoding exon 1 and 1 kb of intron 1, showed clear promoter activity when these fragments were linked to a secreted alkaline phosphatase reporter gene and transfected into a mouse epithelial cell line.
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PMID:Genomic organization of the human beta-catenin gene (CTNNB1). 883 5

The morphology and functions of cells and tissues are determined, in a large part, by mechanical forces generated at cell-cell and cell-extracellular matrix (ECM) contacts. At these sites, transmembrane adhesion receptors of the integrin and cadherin families are linked, via their cytoplasmic domain, to the cytoskeleton by submembranal plaque proteins such as vinculin, alpha-actinin and the cell-cell junctional plaque proteins alpha- and beta-catenin and plakoglobin (or gamma-catenin). Recent studies have implicated this link of structural molecules between the outside and inside of the cell in signal transduction. We have shown that the expression of junctional plaque proteins is modulated during growth stimulation and differentiation, and is dramatically reduced in certain tumor cells. To study the functional significance of these changes in expression, we have used recombinant DNA technologies to overexpress or suppress the levels of junctional plaque proteins. In addition, we eliminated the expression of vinculin in embryonal stem (ES) cells and in the embryonal carcinoma F9 line by gene disruption employing homologous recombination. The results have indicated that moderate overexpression of cell-ECM plaque proteins results in reduced cell motility. In contrast, suppression of their expression, by antisense transfection, led to enhanced motility and conferred anchorage independent growth and tumorigenicity, upon injection into nude mice. These findings suggest that submembranal plaque proteins can act as effective tumor suppressors. In agreement with this notion, we found in several tumor cell lines diminished levels of junctional plaque proteins. Restoration of their level to that found in normal cells resulted in tumor suppression after their injection into experimental animals. Here we demonstrate the usefulness of the application of two dimensional (2-D) gel electrophoresis in these studies.
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PMID:The use of two-dimensional gel electrophoresis in studies on the role of cytoskeletal plaque proteins as tumor suppressors. 898 8

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are linked to both familial and sporadic human colon cancer. So far, a clear biological function for the APC gene product has not been determined. We assayed the activity of APC in the early Xenopus embryo, which has been established as a good model for the analysis of the signaling activity of the APC-associated protein beta-catenin. When expressed in the future ventral side of a four-cell embryo, full-length APC induced a secondary dorsoanterior axis and the induction of the homeobox gene Siamois. This is similar to the phenotype previously observed for ectopic beta-catenin expression. In fact, axis induction by APC required the availability of cytosolic beta-catenin. These results indicate that APC has signaling activity in the early Xenopus embryo. Signaling activity resides in the central domain of the protein, a part of the molecule that is missing in most of the truncating APC mutations in colon cancer. Signaling by APC in Xenopus embryos is not accompanied by detectable changes in expression levels of beta-catenin, indicating that it has direct positive signaling activity in addition to its role in beta-catenin turnover. From these results we propose a model in which APC acts as part of the Wnt/beta-catenin signaling pathway, either upstream of, or in conjunction with, beta-catenin.
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PMID:Adenomatous polyposis coli tumor suppressor protein has signaling activity in Xenopus laevis embryos resulting in the induction of an ectopic dorsoanterior axis. 901 11

beta-Catenin is essential for the function of cadherins, a family of Ca2+-dependent cell-cell adhesion molecules, by linking them to (alpha)-catenin and the actin cytoskeleton. beta-Catenin also binds to adenomatous polyposis coli (APC) protein, a cytosolic protein that is the product of a tumor suppressor gene mutated in colorectal adenomas. We have expressed mutant beta-catenins in MDCK epithelial cells to gain insights into the regulation of beta-catenin distribution between cadherin and APC protein complexes and the functions of these complexes. Full-length beta-catenin, beta-catenin mutant proteins with NH2-terminal deletions before (deltaN90) or after (deltaN131, deltaN151) the alpha-catenin binding site, or a mutant beta-catenin with a COOH-terminal deletion (delta C) were expressed in MDCK cells under the control of the tetracycline-repressible transactivator. All beta-catenin mutant proteins form complexes and colocalize with E-cadherin at cell-cell contacts; deltaN90, but neither deltaN131 nor deltaN151, bind alpha-catenin. However, beta-catenin mutant proteins containing NH2-terminal deletions also colocalize prominently with APC protein in clusters at the tips of plasma membrane protrusions; in contrast, full-length and COOH-terminal-deleted beta-catenin poorly colocalize with APC protein. NH2-terminal deletions result in increased stability of beta-catenin bound to APC protein and E-cadherin, compared with full-length beta-catenin. At low density, MDCK cells expressing NH2-terminal-deleted beta-catenin mutants are dispersed, more fibroblastic in morphology, and less efficient in forming colonies than parental MDCK cells. These results show that the NH2 terminus, but not the COOH terminus of beta-catenin, regulates the dynamics of beta-catenin binding to APC protein and E-cadherin. Changes in beta-catenin binding to cadherin or APC protein, and the ensuing effects on cell morphology and adhesion, are independent of beta-catenin binding to alpha-catenin. These results demonstrate that regulation of beta-catenin binding to E-cadherin and APC protein is important in controlling epithelial cell adhesion.
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PMID:NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion. 902 98

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.
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PMID:Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. 912 80

alpha-Catenin is a 102-kDa protein exhibiting homology to vincuin, and it forms complexes with cadherins or the tumor-suppressor gene product adenomatous polyposis coli through binding to beta-catenin or plakoglobin (gamma-catenin). The incorporation of alpha-catenin into the cadherin-catenin complexes is a prerequisite for expression of the cell-adhesive activity of cadherins. Using an in vitro assay system involving bacterially expressed proteins, we localized a region in alpha-catenin required for molecular interaction with beta-catenin and plakoglobin. Analysis of various truncated alpha-catenin molecules revealed that amino-terminal residues 48-163 are able to bind to beta-catenin and plakoglobin. Consistent with the observation that beta-catenin and plakoglobin bind to the same region of alpha-catenin, beta-catenin competed with the binding of plakoglobin to alpha-catenin and vice versa. Under the conditions used, beta-catenin bound to alpha-catenin with higher affinity than did plakoglobin. Scatchard analysis indicated that the affinity of the interaction between alpha-catenin and beta-catenin or that between alpha-catenin and plakoglobin was moderately strong (Kd = 3. 8 x 10(-8) and 7.7 x 10(-8), respectively). When transfected into L cells expressing E-cadherin, the amino-terminal region of alpha-catenin (from residue 1 to 226) formed complexes with beta-catenin supporting the in vitro binding experiment results.
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PMID:Identification of the domain of alpha-catenin involved in its association with beta-catenin and plakoglobin (gamma-catenin). 911 Sep 93

Epithelial cells are the most important cell type in the development of human malignancies. More than 90% of all malignant tumors are carcinomas, and thus of epithelial origin. Aberrant growth and the ability to invade the underlying tissues are intrinsic properties of the fatally altered cells. Multiple genetic alterations that can influence growth and genetic stability of the carcinoma cells have been characterised during tumor progression. Loss of epithelial morphology and the acquisition of mesenchymal characteristics are typical for carcinoma cells late in tumor progression and correlate with metastatic potential. In vitro, epithelial-mesenchymal transitions can be induced by interference with the integrity of the adherens junction, by signalling via tyrosine kinases, and by oncogene expression. In carcinoma cells, loss or downregulation of E-cadherin expression are frequently observed in carcinomas, and correlate with the malignancy of the tumor. In general, this change in expression is regulated at the transcriptional level. However, tumor types or cell lines exist which show mesenchymal characteristics but nevertheless express E-cadherin protein or mRNA. A more-detailed analysis demonstrated that other mechanisms that interfere with E-cadherin-mediated cell adhesion can be operative. Mutations in the E-cadherin gene and loss or mutation of the second, intact copy as well as mutation in the catenin genes, which encode proteins that interact with the cytoplasmic portion of E-cadherin, can be observed. In addition, transient or unregulated phosphorylation by receptor tyrosine kinases or oncogenic tyrosine kinases, respectively, can interfere with the epithelial morphology and induce a mesenchymal conversion. Since tyrosine phosphorylation of beta-catenin correlates with the epithelial-mesenchymal transition that is observed, E-cadherin-mediated cell adhesion might be modulated by such a mechanism. Interestingly, the same molecules implicated in the control of malignant properties turn out to play fundamental roles in the control of normal epithelial growth, differentiation and morphogenesis.
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PMID:Epithelial-mesenchymal transitions in cancer progression. 912 38

Reductions in cell-cell adhesion and stromal and vascular invasion are essential steps in the progression from localized malignancy to metastatic disease. In this study, changes in the expression of the components of the E-cadherin-catenin cell adhesion complex have been investigated using immunohistochemical techniques in primary tumours and nodal metastases from 36 patients with squamous cell carcinoma of the head and neck. For 14 patients the corresponding primary and nodal metastases samples were available. None of the 51 samples showed normal E-cadherin expression when compared with either the adjacent normal squamous epithelium or with normal colonic epithelium that was used as positive control material. In 88% of primary tumours fewer than 50% of cells exhibited normal membranous E-cadherin expression. Loss of membranous E-cadherin expression was more extensive in poorly differentiated carcinomas while, in individual carcinomas, membranous E-cadherin expression was stronger in those parts of the neoplasm that expressed the differentiation marker involucrin. Expression of beta-catenin generally paralleled that of E-cadherin, but in 12 cases there was strong membranous beta-catenin expression in samples that exhibited predominantly cytoplasmic E-cadherin labelling. Expression of alpha-catenin was generally weak and did not correlate with the expression of either beta-catenin or E-cadherin. Marked intratumoral heterogeneity for protein expression was evident for all antibodies, and the abnormal expression of the catenins is a novel finding. E-cadherin is expressed more intensely in cells with greater squamous differentiation, but there was no correlation between the decreased expression of any of the adhesion molecules of the E-cadherin complex tested and local recurrence, metastasis or survival. The loss of expression of components of the E-cadherin complex is a common abnormality in squamous carcinomas and, while it may be permissive for metastasis, it does not appear to be the only determinant of this process.
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PMID:Expression of the E-cadherin-catenin cell adhesion complex in primary squamous cell carcinomas of the head and neck and their nodal metastases. 916 40

Previous studies reported that the overexpression of the epidermal growth factor receptor (EGF-R) and reduced expression of E-cadherin and alpha-catein were associated with lymph node metastasis of the esophageal cancer. In the present study, we examined that epidermal growth factor (EGF) caused in part the dysfunction of cadherin-mediated cell-cell adhesion using the human esophageal cancer cell line (TE-2R), which expressed E-cadherin and EGF-R. In the presence of EGF, TE-2R changed its colony formation from compact to sparse. In the cell dissociation assay, EGF strongly facilitated the dissociation of TE-2R cells in a dose-dependent manner. Moreover, EGF enabled the cells to invade in organotypic raft culture. These phenomena were accompanied not by decreased expression of the E-cadherin molecule but by a change in its localisation from the lateral adhesion site to the whole cell surface. Finally, we observed tyrosine phosphorylation of beta-catenin induced by EGF. These results might suggest that EGF counteracts E-cadherin mediated cell-cell adhesion through phosphorylation of beta-catenin and modulates tumor cell behaviour to a more aggressive phenotype for lymph node metastasis of the esophageal cancer.
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PMID:[Mechanism of the lymph node metastasis in human esophageal cancer (epidermal growth factor causes the dysfunction of cadherin-mediated cell-cell adhesion)]. 918 27

Defects in the APC gene are inarguably linked to the progression of colon cancers that arise both sporadically and through the transmission of germline mutations. Genetic evidence from humans and mouse models suggest that APC is a classic tumor suppressor in that both alleles likely require inactivation for tumor growth to ensue. Nearly all of the mutations, germline and somatic, result in premature termination of the single polypeptide chain, normally consisting of 2843 amino acids. Several definable motifs have now been mapped to the linear amino acid sequence of the APC polypeptide. These include an oligomerization domain, armadillo repeats, binding sites for beta-catenin, the human discs large protein, microtubules, and other proteins of unknown function. Inactivation of APC in cancer is likely due to loss of function(s) normally associated with the deleted protein structure.
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PMID:The adenomatous polyposis coli (APC) tumor suppressor. 919 22


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