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)

Genetic and epigenetic alterations of multiple cancer-related genes and molecules are implicated in the development and progression of human gastric carcinomas. Reactivation of telomerase, inactivation of p53 tumor suppressor gene, overexpression of cyclin E, and reduced expression of p27 KIP1 by disorganized degradation in proteasome are common events of both well-differentiated and poorly differentiated gastric adenocarcinomas. Inactivation of hMLH1 mismatch repair gene by CpG hypermethylation resulting in microsatellite instability, amplification of c-erbB2 oncogene, inactivation of APC tumor suppressor gene, and K-ras mutations are preferentially associated with well-differentiated gastric cancer. Conversely, reduction or loss of E-cadherin and catenins by both mutation and CpG hypermethylation and K-sam and c-met oncogene amplification are necessary for the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cancer cells expressing c-met and hepatocyte growth factor from stromal cells is implicated in morphogenesis of gastric cancer.
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PMID:Genetic and epigenetic changes in stomach cancer. 1124 97

The effect of HGF/SF was examined on the interactions between APC, GSK3beta and beta-catenin in prostate cancer cells LNCapFGC (E-cadherin positive) and PC-3 (E-cadherin negative). Using immunoprecipitation, APC was found to be co-precipitated with either GSK3beta or beta-catenin in both cell lines. Stimulation with HGF/SF showed no change in the co-precipitation status of these protein molecules. In contrast, co-precipitation between GSK3beta and beta-catenin was only observed in LNCapFGC cells, and increased upon continued exposure to the motogen HGF/SF. Furthermore, using immunofluorescence, stimulation with HGF/SF was found to increase the level of co-localised cytoplasmic staining between beta-catenin and GSK3beta, in prostate cancer cells. RT-PCR revealed that there were no mutations within the binding regions between beta-catenin and GSK3beta. It is concluded, that uncomplexed cytoplasmic pools of beta-catenin associate more readily with the Axin complex in the absence of E-cadherin. Whereas, in the presence of E-cadherin, beta-catenin is stabilised by forming tight cell-cell contacts which may influence the invasive potential of cancer cells.
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PMID:The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer. 1125 Nov 83

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

The beta-catenin TCF pathway is implicated in the regulation of colonic epithelial cell proliferation, but its role in the regulation of cell differentiation is unknown. The colon carcinoma cell line, Caco-2, spontaneously undergoes G(0)/G(1) cell cycle arrest and differentiates along the absorptive cell lineage over 21 days in culture. In parallel, we show that beta-catenin-TCF activity and complex formation are significantly down-regulated. The down-regulation of beta-catenin-TCF signaling was independent of APC, which we characterized as having a nonsense mutation in codon 1367 in Caco-2 cells, but was associated with a decrease in TCF-4 protein levels. Total beta-catenin levels increased during Caco-2 cell differentiation, although this was attributable to an increase in the membrane, E-cadherin-associated, fraction of beta-catenin. Importantly, down-regulation of beta-catenin-TCF signaling in undifferentiated Caco-2 cells by three different mechanisms, ectopic expression of E-cadherin, wild-type APC, or dominant negative TCF-4, resulted in an increase in the promoter activities of two genes that are well-established markers of cell differentiation, alkaline phosphatase and intestinal fatty acid binding protein. These studies demonstrate, therefore, that in addition to its established role in the regulation of cell proliferation, down-regulation of the beta-catenin-TCF pathway is associated with the promotion of a more-differentiated phenotype in colonic epithelial cells.
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PMID:Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. 1130 9

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

To evaluate the genetic factors of familial predisposition to gastric cancer, genetic alterations in the surgically resected stomach samples from gastric-cancer-prone families were investigated. Familial gastric cancer (FGC) was defined as gastric cancer occurring in a family with 3 or more gastric cancer patients over at least two successive generations. We examined replication error (RER) of six microsatellite markers and screened mutations of the 10-(A) repeat sequence in the transforming growth factor-beta receptor type II (TGF-betaRII) gene in individuals from seven unrelated FGC families. Three cases showed RER at one of the six (CA)n microsatellite markers but the other 4 cases showed no RER at any of these loci. No mutation was found in the 10-(A) repeat of the TGF-betaRII gene. Additionally, no germline mutation was found by polymerase chain reaction-single strand conformation polymorphism in exons 1-16 of E-cadherin, exons 5-8 of p53 and in the mutation cluster region of APC. These results indicate that disorders in the DNA mismatch repair system, E-cadherin, p53 and APC may be infrequently involved in the carcinogenesis of Japanese FGC.
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PMID:Absence of microsatellite instability and germline mutations of E-cadherin, APC and p53 genes in Japanese familial gastric cancer. 1139 52

Promoter hypermethylation is an important pathway for the repression of gene transcription in cancer. We investigated promoter hypermethylation of six genes, p16, APC, HIC-1, death-associated protein kinase (DAPK), O(6)-methylguanine-DNA-methyltransferase (MGMT), and E-cadherin, in uterine cervical carcinoma from 53 patients including 31 cases of squamous cell carcinoma (SCC) and 22 cases of adenocarcinoma (AC). Aberrant methylation of at least one of these genes was detected in 79% (42 of 53) of cases including 71% (22 of 31) of SCC and 91% (20 of 22) of AC cases. No aberrant methylation was detected in normal cervical tissue from 24 control hysterectomy specimens. There was no correlation between promoter hypermethylation at any gene and the presence of human papillomavirus-16 or -18 E7 DNA. In AC cases, promoter hypermethylation of the APC and HIC-1 genes was detected at a statistically significant higher frequency than in the SCC cases (APC, 60% versus 13%, P < 0.001; HIC-1, 63% versus 32%, P < 0.03). Conversely, promoter hypermethylation of p16 and DAPK was more common in SCC cases than in AC cases. Our results suggest that promoter hypermethylation is a frequent epigenetic event in cervical carcinoma. The pattern of gene promoter hypermethylation is distinctly different between AC and SCC. The absence of these epigenetic alterations in normal cervical tissue suggests that they may also be valuable as cancer markers.
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PMID:Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. 1144 14

We established a yeast-based method to screen chain-terminating mutations that is readily applicable to any gene of interest. Based on the finding that 18- to 24-base-long homologous sequences are sufficient for gap repair in vivo in yeast, we used a strategy to amplify a test-gene fragment with addition of 24-bp sequences homologous to both cut-ends of a yeast expression vector, pMT18. After co-transformation with the amplified fragment and the linearized pMT18, each yeast (Saccharomyces cerevisiae) cell automatically forms a single-copy circular plasmid (because of CEN/ARS), which expresses a test-gene::ADE2 chimera protein. When the reading frame of the test-gene contains a nonsense or frameshift mutation, truncation of the chimera protein results in lack of ADE2 activity, leading to formation of a red colony. By using a nested polymerase chain reaction using proofreading Pfu polymerase to ensure specificity of the product, the assay achieved a low background (false positivity). We applied the assay to BRCA1, APC, hMSH6, and E-cadherin genes, and successfully detected mutations in mRNA and genomic DNA. Because this method--universal stop codon assay--requires only 4 to 5 days to screen a number of samples for any target gene, it may serve as a high-throughput screening system of general utility for chain-terminating mutations that are most prevalent in human genetic diseases.
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PMID:Development of a yeast stop codon assay readily and generally applicable to human genes. 1158 51

Observations support the theory that development of left- and right-sided colorectal cancers may involve different mechanisms. This study investigated different genes involved in oncogenesis of colon and rectal cancers and analysed their prognostic value. The study group comprised 35 colon and 42 rectal cancers. Rectal cancer patients had been treated with standardized surgery performed by an experienced rectal cancer surgeon. Mutation analysis was performed for p53 in eight colon cancers and for APC and p53 in 22 rectal cancers. MLH1, MSH2, Bcl-2, p53, E-cadherin and beta-catenin were investigated by immunohistochemistry in all colorectal tumours. APC mutation analysis of the MCR showed truncating mutations in 18 of 22 rectal tumours (82%), but the presence of an APC mutation was not related to nuclear beta-catenin expression (p=0.75). Rectal cancers showed significantly more nuclear beta-catenin than colon cancers (65% versus 40%, p=0.04). p53 mutation analysis corresponded well with p53 immunohistochemistry (p<0.001). Rectal cancers showed significantly more immunohistochemical expression of p53 than colon cancers (64% versus 29%, p=0.003). In rectal cancers, a significant correlation was found between positive p53 expression and worse disease-free survival (p=0.008), but not in colon cancers. Cox regression showed that p53-expression (p=0.03) was an independent predictor for disease-free survival in rectal cancers. This study concluded that rectal cancer may involve more nuclear beta-catenin in the APC/beta-catenin pathway than colon cancer and/or nuclear beta-catenin may have another role in rectal cancer independently of APC. The p53-pathway seems to be more important in rectal cancer, in which it also has independent prognostic value. When prognostic markers are investigated in larger series, differences in biological behaviour between colon and rectal cancer should be considered.
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PMID:Mechanisms of oncogenesis in colon versus rectal cancer. 1159 95

Aberrant signalling activities of beta-catenin, originally identified as a component of cell-adhesion complexes, are now considered to be an important factor in colorectal carcinogenesis. However, recently it was shown that also gamma- as well as p120 catenins have a dual role either in cell adhesion or in affecting some gene activation. Therefore, the levels and interactions of these three catenins in human colorectal carcinoma cell lines were analysed. A great heterogeneity in the expression of all catenins tested was found in colorectal carcinoma cell lines HT29 and LS174T. Detailed analysis of beta-catenin interactions was done. GST-APC fragment-fused proteins were used to absorb beta-catenin and its complexes from cell lysates. Similarly, the E-cadherin binding capacity of the residual pool of beta-catenin was analysed using the GST-ECT construct. It was found that the level of beta-catenin does not necessarily depend either on the APC or beta-catenin gene mutations and that co-precipitation of beta-, gamma-, and p120 catenins is not limited to cells that express E-cadherin.
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PMID:Expression and interaction of different catenins in colorectal carcinoma cells. 1171 88


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