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)

The human EB1 gene product was recently found, by a yeast two-hybrid screening, to be associated with the carboxy terminus of the APC (adenomatous polyposis coli) protein, the product of a tumour-suppressor gene thought to act as a gatekeeper in colorectal carcinogenesis. Because virtually all of the APC mutations result in the synthesis of carboxy-terminal truncated proteins, mutant APC proteins are expected to lose their ability to interact with EB1 gene product. Thus, the interaction between APC and EB1 proteins may be important for the tumour-suppressor activity of APC protein, and raises the hypothesis that EB1 is also involved in sporadic colorectal tumorigenesis. To investigate this hypothesis, somatic mutations in the entire coding sequence of EB1 cDNA were searched by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven adenomas. None of these tumours contained somatic mutation, whereas a silent cDNA variant was identified in 14% of alleles. Furthermore, to investigate whether EB1 locus was included within a region subjected to losses of heterozygosity, four polymorphism markers surrounding EB1 locus were surveyed. Only one out of 28 colorectal tumours contained a loss of heterozygosity at the D20S107 marker. In conclusion, the present findings strongly suggest that EB1 gene is not involved in somatic colorectal carcinogenesis.
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PMID:Absence of somatic alterations of the EB1 gene adenomatous polyposis coli-associated protein in human sporadic colorectal cancers. 982 79

Small adenocarcinomas of the colorectum showing no evidence of origin from an adenoma have been called de novo carcinomas, a name that implies an origin via a different molecular genetic mechanism than the usual colorectal carcinoma which develops from an adenoma. Using microsatellite analysis, 35 early (pT1) de novo and 36 pT1 ex-adenoma carcinomas were compared using 8 microsatellite loci at 6 different chromosomal loci (1p, 2p, 8p, 5q, 17p, and 18q) known or hypothesized to be important for colorectal carcinogenesis. The rate of loss of heterozygosity (LOH) at the 17p locus (near the p53 gene) was significantly higher in the de novo than in the ex-adenoma group (73 vs. 37%, P = 0.004). The rates of LOH at the other loci (including the APC and DCC genes) and the rate of MSI were not significantly different in the two groups. These results indicate that de novo carcinomas of the colorectum develop via a similar carcinogenetic pathway as conventional ex-adenoma carcinomas; however, their higher rate of LOH at 17p is evidence for a biologically more advanced lesion with more frequent p53 mutations, consistent with clinicopathological data indicating that de novo carcinomas are more aggressive than ex-adenoma carcinomas.
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PMID:Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum. 984 87

Tcf-4 is a member of the Tcf/Lef family of transcription factors that interact functionally with beta-catenin to mediate Wnt signaling in vertebrates. We have previously demonstrated that the tumor suppressor function of APC in the small intestine is mediated via regulation of Tcf-4/beta-catenin transcriptional activity. To gain further insight into the role of Tcf-4 in development and carcinogenesis we have generated several mouse monoclonal antibodies, one of which is specific for Tcf-4 and another of which recognizes both Tcf-3 and Tcf-4. Immunohistochemistry performed with the Tcf 4- specific monoclonal antibody revealed high levels of expression in normal intestinal and mammary epithelium and carcinomas derived therefrom. Additional sites of Tcf-3 expression, as revealed by staining with the Tcf-3/-4 antibody, occurred only within the stomach epithelium, hair follicles, and keratinocytes of the skin. A temporal Tcf-4 expression gradient was observed along the crypt-villus axis of human small intestinal epithelium: strong Tcf-4 expression was present within the crypts of early (week 16) human fetal small intestine, with the villi showing barely detectable Tcf-4 protein levels. Tcf-4 expression levels increased dramatically on the villi of more highly developed (week 22) fetal small intestine. We conclude that Tcf-4 exhibits a highly restricted expression pattern related to the developmental stage of the intestinal epithelium. The high levels of Tcf-4 expression in mammary epithelium and mammary carcinomas may also indicate a role in the development of this tissue and breast carcinoma.
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PMID:Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium. 991 15

Serrated adenoma has been recently proposed as a distinct histological lesion of the colorectum. This study examined p53 immunoreactivity, mutations of exons 5-8 of the p53 gene, codon 12 of the Ki-ras gene by PCR-SSCP analyses, and microsatellite instability in 19 serrated adenomas, ten adenocarcinomas in/with serrated adenomas, 23 hyperplastic nodules, four hyperplastic polyps and 29 tubular adenomas of the colorectum. Eleven of 11 (100 per cent) serrated adenomas had p53 immunoreactivity and all six (100 per cent) adenocacinomas in/with serrated adenomas exhibited moderate to severe p53 immunoreactivity. It was confirmed that 9 of 19 (47 per cent) serrated adenomas and 5 of 10 (50 per cent) adenocarcinomas in/with serrated adenomas harboured p53 gene mutations. On the other hand, no p53 gene mutation was detected in the other colorectal lesions. Meanwhile, 11 (58 per cent) serrated adenomas and six (60 per cent) adenocarcinomas in/with serrated adenomas had Ki-ras gene mutations, as also did 9 of 23 (39 per cent) hyperplastic nodules, 3 of 4 (75 per cent) hyperplastic polyps, and 12 of 29 (41 per cent) tubular adenomas. Microsatellite instability was detected in one (5 per cent) serrated adenoma and one (10 per cent) adenocarcinoma in a serrated adenoma. The other lesions did not show microsatellite instability. Serrated adenomas had significantly frequent p53 gene mutations compared with hyperplastic lesions or tubular adenomas (p < 0.005). On the other hand, they did not exhibit significant differences in mutations of the Ki-ras gene or in microsatellite instability. Genetic changes were then examined in small parts of serrated adenomas, such as the upper or lower parts of crypts, to determine the extent of gene mutations by using a microdissection technique. Exon 15 of the APC gene and the DCC gene, in addition to the p53 and Ki-ras genes and microsatellite instability, were analysed. Identical mutations of the p53 gene were found in both invasive adenocarcinomas and adjacent serrated adenomas by direct sequencing, suggesting single clonal origins for those lesions. Mutations of the APC gene and microsatellite instability were heterogeneous in some lesions. No loss of heterozygosity (LOH) of the DCC gene was found. These findings suggest that mutations of the p53 gene are the most characteristic genetic alterations in serrated adenomas, as a relatively early event in a multistep carcinogenic pathway of this type of colorectal lesion, that might be distinct from the ordinary adenoma-carcinoma sequence or from carcinogenesis via mutations of mismatch repair genes.
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PMID:Frequent p53 gene mutations in serrated adenomas of the colorectum. 992 27

Germ-line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine-->lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and.or colorectal cancer, for the APC I1307K polymorphism. The APC I1307K allele was identified in 48 (10.1%) of 476 patients. Compared with the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.5-1.7 for colorectal neoplasia (both P=.01). Furthermore, compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P=.03), as well as a younger age at diagnosis. We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for the 360,000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colorectal cancer prevention in this population.
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PMID:Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism. 997 76

Variations in the length of simple repetitive tandem repeats (microsatellite instability, MIN) between constitutive and tumour DNA, which is characteristic of tumours in patients affected with hereditary nonpolyposis colon cancer (HNPCC), have been found to be very important in the carcinogenesis of a variety of human neoplasms. Recently, MIN has been found in sebaceous and colorectal tumours as well as in keratoacanthomas of Muir-Torre syndrome. In order to elucidate the significance of both MIN and loss of heterozygosity (LOH) in the pathogenesis of sporadic keratoacanthomas, the presence of MIN and LOH at five loci [chromosome 5q21 (D5S346, APC), 9p21 (D9S171, p16), 10pter (D10S89, Mfd28), 11p (D11S904) and 17p12 (D17S520, p53)] was evaluated. MIN was found at only one locus (p53) in 1 of 12 keratoacanthomas and no evidence for the presence of LOH could be detected. Our results suggest that, in contrast to keratoacanthomas associated with Muir-Torre syndrome, neither MIN nor LOH appear to be significant in the induction of sporadic keratoacanthomas.
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PMID:Assessment of microsatellite instability and loss of heterozygosity in sporadic keratoacanthomas. 1002 21

beta-Catenin has 2 distinct roles in E-cadherin-mediated cell adhesion and carcinogenesis through APC gene mutation. One occurs at cell-adhesion sites, where cadherins become linked to the actin-based cytoskeleton. The others occur in the cytoplasm and nuclei and are thought to regulate cell transformation. We studied these different beta-catenins and evaluated their significance in carcinogenesis. Fresh surgical specimens were obtained from 22 patients with squamous-cell carcinoma of the esophagus. beta-Catenin in the free soluble fraction and the insoluble fraction was immunoblotted separately. At the same time, its localization was observed by immuno-histochemical techniques. In the normal esophageal epithelium, 91% of beta-catenin was detected in the insoluble fraction and beta-catenin staining occurred at the cell membrane, in co-existence with E-cadherin. In cancerous tissues, the amount of soluble beta-catenin was significantly (about 4-fold) higher than in normal tissues. Also, in cancerous tissues with higher amounts of soluble beta-catenin, immuno-histochemical techniques revealed the presence of beta-catenin in the cytoplasm and nuclei, as well as in the cell membrane. However, in samples with lower amounts of beta-catenin, expression was found only at the cell boundaries. The amount of soluble beta-catenin was not associated with the clinico-pathological grading of the tumors. Our results show that the accumulation of free soluble beta-catenin in the cytoplasm and nuclei frequently occurs during carcinogenesis of the squamous epithelium of the esophagus.
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PMID:Cytoplasmic beta-catenin in esophageal cancers. 1009 51

Dysfunction of the cadherin-mediated cell adhesion system involved in cancer metastasis occurs by several mechanisms: alterations of E-cadherin, alpha- and beta-catenin genes, CpG methylation of the promoter region of E-cadherin, and aberrant tyrosine phosphorylation of beta-catenin. In addition to the cell adhesion function, beta-catenin, which is an intracytoplasmic cadherin binding molecule and thought to be a regulator of cadherin-mediated cell adhesion function, has been proven to associate with both the growth factor receptors, including c-erbB-2, EGF receptor and k-sam and APC tumor suppressor gene product. These data indicate that the cadherin-mediated cell adhesion system plays important roles not only in cancer metastasis but in carcinogenesis.
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PMID:[Dysfunction of cadherin cell adhesion system in cancer invasion and metastasis]. 1009 60

Wnt-1 acts as a mammary oncogene when ectopically expressed in the mouse mammary gland. APC is a tumor suppressor gene, mutations in which cause intestinal tumorigenesis in humans and rodents. Both Wnt-1 expression and APC mutation activate a common signaling pathway involving transcriptional activation mediated by beta-catenin/Tcf complexes, but few targets relevant to carcinogenesis have yet been identified. Expression of the inducible prostaglandin synthase cyclooxygenase-2 appears critical for intestinal tumorigenesis resulting from APC mutation, suggesting that cyclooxygenase-2 might be a transcriptional target for beta-catenin/Tcf complexes. Here, we have investigated the effect of Wnt-1 on cyclooxygenase-2 expression. Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG induces stabilization of cytosolic beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the cyclooxygenase-2 gene, resulting in increased levels of cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated cyclooxygenase-2 activity and could be decreased by treatment with a selective cyclooxygenase-2 inhibitor. Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and Wnt-1 expression. In view of the critical role of cyclooxygenase-2 in intestinal tumorigenesis, cyclooxygenase-2 up-regulation in response to Wnt signaling may contribute to Wnt-induced mammary carcinogenesis.
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PMID:Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. 1019 31

Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an oncogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1. In this study, mutations in the region corresponding to N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene were investigated in 20 colon tumors associated with ulcerative colitis and induced with methylazoxymethanol acetate and 1-hydroxyanthraquinone. Ninety percent (18 of 20) of the tumors induced in male F344 rats harbored mutations, which were detected in three of four adenomas (75%) and 15 of 16 adenocarcinomas (94%). Of 18 total missense mutations, 13 (72%) were G-->A transitions at position 101, three were G-->A transitions at position 94, and two were C-->T transitions at position 122, resulting in the amino acid substitutions Gly34-->Glu, Asp32-->Asn, and Thr41-->Ile, respectively. Although there were no mutations in the Apc gene, as we previously reported in the same tumor samples, the results obtained in this study strongly implicate the Apc-beta-catenin-T-cell factor (Tcf) signaling pathway in methylazoxymethanol acetate, 1-hydroxyanthraquinone-induced colon carcinogenesis.
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PMID:Frequent mutations of the rat beta-catenin gene in colon cancers induced by methylazoxymethanol acetate plus 1-hydroxyanthraquinone. 1020 8


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