Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadherins are transmembrane cell-cell adhesion molecules which are connected to the cytoskeleton by association with the cytoplasmic proteins, alpha-, beta-, and, gamma-catenin (plakoglobin). Beta-catenin has an additional role in the wnt signal transduction pathway in which it transmitts signals to the cell nucleus in complexes with transcription factors of the LEF-1/TCF family. The cell adhesion function of the epithelial E-cadherin is frequently disturbed in carcinomas either by downregulation or by mutation of the E-cadherin/catenin genes. The signaling function of beta-catenin is activated in tumors by mutations of beta-catenin or of the tumor suppressor gene product APC. In this review I will give an introduction to the structure and function of the cadherin/catenin complex and summarize findings which support a decisive role of these components in the development of cancer.
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PMID:Cadherins and catenins: role in signal transduction and tumor progression. 1050 43

We describe the assembly of a cosmid and PAC contig of approximately 700 kb on human chromosome 18q12 spanning the DSC and DSG genes coding for the desmocollins and desmogleins. These are members of the cadherin superfamily of calcium-dependent cell adhesion proteins present in the desmosome type of cell junction found especially in epithelial cells. They provide the strong cell-cell adhesion generated by this type of cell junction for which expression of both a desmocollin and a desmoglein is required. In the autoimmune skin diseases pemphigus foliaceous and pemphigus vulgaris (PV), where the autoantigens are, respectively, encoded by the DSG1 and DSG3 genes, severe areas of acantholysis (cell separation), potentially life-threatening in the case of PV, are evident. Dominant mutations in the DSG1 gene causing striate palmoplantar keratoderma result in hyperkeratosis of the skin on the parts of the body where pressure and abrasion are greatest, viz., on the palms and soles. These genes are also candidate tumor suppressor genes in squamous cell carcinomas and other epithelial cancers. We have screened two chromosome 18-specific cosmid libraries by hybridization with previously isolated YAC clones and DSC and DSG cDNAs, and a whole genome PAC library, both by hybridization with the YACs and by screening by PCR using cDNA sequences and YAC end sequence. The contigs were extended by further PCR screens using STSs generated by vectorette walking from the ends of the cosmids and PACs, together with sequence from PAC ends. Despite screening of two libraries, the cosmid contig still had four gaps. The PAC contig filled these gaps and in fact covered the whole locus. The positions of 45 STSs covering the whole of this region are presented. The desmocollin and desmoglein genes, which are about 30-35 kb in size, are quite well separated at approximately 20-30 kb apart and are arranged in two clusters, one DSC cluster and one DSG cluster, which are transcribed outward from the interlocus region. The order of the genes is correlated with the spatial order of gene expression in the developing mouse embryo, and this, and previous transgenic experiments, suggests that long-range genetic elements that coordinate expression of these genes may be present. The complete bacterial clone contig described in this paper is thus a resource not only for future sequencing but also for investigations into the control of expression of these clustered genes.
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PMID:Clustered cadherin genes: a sequence-ready contig for the desmosomal cadherin locus on human chromosome 18. 1064 42

beta-catenin regulates cadherin-mediated cell-cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E-cadherin, alpha-catenin and beta-catenin in 22 cases of esophageal squamous-cell carcinoma by Western-blot analysis. Expression of E-cadherin, alpha-catenin and beta-catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E-cadherin, 6 cases (27.3%) for alpha-catenin and 9 cases (40.9%) for beta-catenin. Expression of beta-catenin was not always correlated with that of E-cadherin. Over-expression of beta-catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over-expression of beta-catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of beta-catenin was observed in one case that had higher beta-catenin level in tumor tissue (1.4-fold higher than normal mucosa). The genomic DNA sequences of the beta-catenin and the APC gene were analyzed. No mutation of the beta-catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over-expression or nuclear localization of the beta-catenin protein. These results indicate that alterations of the cadherin-catenin complex may play an important role in a sub-set of esophageal carcinogenesis. Furthermore, it is suggested that beta-catenin over-expression is not caused by genetic alteration of either the beta-catenin or the APC gene.
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PMID:Alteration of beta-catenin expression in esophageal squamous-cell carcinoma. 1070 91

The Wnt signaling pathway plays critical roles in embryonic development and tumorigenesis. Stimulation of the Wnt pathway results in the accumulation of a nuclear beta-catenin/Tcf complex, activating Wnt target genes. A crystal structure of beta-catenin bound to the beta-catenin binding domain of Tcf3 (Tcf3-CBD) has been determined. The Tcf3-CBD forms an elongated structure with three binding modules that runs antiparallel to beta-catenin along the positively charged groove formed by the armadillo repeats. Structure-based mutagenesis defines three sites in beta-catenin that are critical for binding the Tcf3-CBD and are differentially involved in binding APC, cadherin, and Axin. The structural and mutagenesis data reveal a potential target for molecular drug design studies.
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PMID:Crystal structure of a beta-catenin/Tcf complex. 1113 74

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.
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PMID:Molecular characterization of undifferentiated-type gastric carcinoma. 1130 79

As a component of adherens junctions and the Wnt signaling pathway, beta-catenin binds cadherins, Tcf family transcription factors, and the tumor suppressor APC. We have determined the crystal structures of both unphosphorylated and phosphorylated E-cadherin cytoplasmic domain complexed with the arm repeat region of beta-catenin. The interaction spans all 12 arm repeats, and features quasi-independent binding regions that include helices which interact with both ends of the arm repeat domain and an extended stretch of 14 residues which closely resembles a portion of XTcf-3. Phosphorylation of E-cadherin results in interactions with a hydrophobic patch of beta-catenin that mimics the binding of an amphipathic XTcf-3 helix. APC contains sequences homologous to the phosphorylated region of cadherin, and is likely to bind similarly.
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PMID:The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. 1134 95

Human beta-catenin and its fly homolog Armadillo are best known for their roles in cadherin-based cell-cell adhesion and in transduction of Wingless/Wnt signals. It has been hypothesized that beta-catenin may also regulate cell migration and cell shape changes, possibly by regulating the microtubule cytoskeleton via interactions with APC. This hypothesis was based on experiments in which a hyperstable mutant form of beta-catenin was expressed in MDCK cells, where it altered their migratory properties and their ability to send out long cellular processes. We tested the generality of this hypothesis in vivo in Drosophila. We utilized three model systems in which cell migration and/or process extension are known to play key roles during development: the migration of the border cells during oogenesis, the extension of axons in the nervous system, and the migration and cell process extension of tracheal cells. In all cases, cells expressing activated Armadillo were able to migrate and extend cell processes essentially normally. The one alteration from normal involved an apparent cell fate change in certain tracheal cells. These results suggest that only certain cells are affected by activation of Armadillo/beta-catenin, and that Armadillo/beta-catenin does not play a general role in inhibiting cell migration or process extension.
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PMID:Activated armadillo/beta-catenin does not play a general role in cell migration and process extension in Drosophila. 1141 25

Among the hallmarks of cancer are defective cell-cell and cell-matrix adhesion. Alterations in cadherin-catenin complexes likely have a major contributing role in cell-adhesion defects in carcinomas arising in many different tissues. E-cadherin, the prototypic member of the cadherin transmembrane protein family, regulates cell adhesion by interacting with E-cadherin molecules on opposing cell surfaces. E-cadherin's function in cell adhesion is also critically dependent on its ability to interact through its cytoplasmic domain with catenin proteins. A diverse collection of defects alter cadherin-catenin function in cancer cells, including loss-of-function mutations and defects in the expression of E-cadherin and certain catenins, such as alpha-catenin. Although there is much evidence that beta-catenin is deregulated in cancer as a result of inactivating mutations in the APC and AXIN tumor-suppressor proteins and gain-of-function mutations in beta-catenin itself, the principal consequences of beta-catenin deregulation in cancer appear to be largely distinct from the effects attributable to inactivation of E-cadherin or alpha-catenin. In this review, we highlight some of the specific genetic and epigenetic defects responsible for altered cadherin and catenin function in cancer, as well as potential contributions of cadherin-catenin alterations to the cancer process.
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PMID:Cadherin and catenin alterations in human cancer. 1200 86

beta-Catenin is an intracellular multifunctional protein. In complex with the transmembrane adhesive receptor E-cadherin, it becomes plasma membrane-associated and mediates intercellular adhesion. A cytosolic pool of beta-catenin interacts with DNA-binding proteins and participates in signal transduction. To reveal the possible cross-talk between these two pools, we studied whether beta-catenin is exchanged between its free and cadherin-bound states. We found that pulse-labeled beta-catenin replaces the beta-catenin bound to the cell surface prebiotinylated E-cadherin immediately after synthesis. Approximately 25% of all pulse-labeled beta-catenin destined for E-cadherin associates with this protein via this mechanism. The rest of the newly synthesized beta-catenin arrives at the plasma membrane in a complex with the E-cadherin precursor. Immediately after arrival, this beta-catenin pool is transferred to the prebiotinylated E-cadherin. beta-Catenin released from E-cadherin may participate in new exchange cycles. This beta-catenin exchange is strongly affected in cells that contain mutations in the tumor suppressor gene APC. This process may contribute significantly to both cell-cell adhesion and beta-catenin-dependent signaling.
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PMID:Exchange of catenins in cadherin-catenin complex. 1260 44

Beta-catenin is an undercoat protein of cadherin, a cellular adhesion molecule. Beta-catenin also functions as a transcriptional activator downstream of the Wnt signaling pathway. Intracellular beta-catenin is regulated by the formation of a complex with APC (adenomatous polyposis coli) protein. The activation of this pathway by stabilization with beta-catenin has been shown to be an important step in the development of colorectal carcinoma, which is mainly caused by inactivating mutations in the APC tumor suppressor gene or by activating mutations in exon 3 of the beta-catenin gene. This study was conducted to clarify the contribution of beta-catenin accumulation and the mutation of the beta-catenin gene to the carcinogenesis of head and neck cancer. Beta-catenin accumulation was examined immunohistochemically in 49 frozen or formalin-fixed, paraffin-embedded samples of head and neck tumors. We also performed a direct sequence analysis of APC and beta-catenin to examine the cause of beta-catenin accumulation. Genomic DNA was extracted and purified from fresh tissue samples of head and neck cancers. We examined the APC mutation cluster region in 15 samples and analyzed beta-catenin exon 3 mutations in 31 cases. Twelve out of 49 (24.5%) cases exhibited beta-catenin accumulation in our histochemical study. The 5 year survival rate was 0% in the beta-catenin accumulation group, compared to 50% in the non-accumulation group, (p < 0.01). This finding strongly suggests that beta-catenin may play an important role in the carcinogenesis or progression of head and neck cancer. One of the 15 cases exhibited an APC missense mutation that led to the replacement of amino acids; this case died in 12 months. Regarding the beta-catein mutation, non of the 31 samples exhibited a gene mutation in beta-catenin exon 3. Thus, the rate of APC and beta-catenin mutation in head and neck cancer may be very low.
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PMID:[Roles of beta-catenin overexpression and adenomatous polyposis coli mutation in head and neck cancer]. 1287 24


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