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)

Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years. Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli. In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential. In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased beta-catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas. Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples. Our data indicate for the first time that beta-catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the beta-catenin gene may substitute biallelic APC inactivation in this tumor type. Genes Chromosomes Cancer 25:399-402, 1999.
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PMID:Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. 1039 36

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is the most frequent extraintestinal manifestation of familial adenomatous polyposis. Present in 70% of families with familial adenomatous polyposis, CHRPE is a highly reliable and early marker of the disease. Studies over the past 5 years have addressed the histologic characteristics of the pigmented fundus lesions, the definition of universal positive fundus criteria, and mostly the genotype-phenotype correlation. Indeed, the position of the mutation site of the APC (adenomatous polyposis coli) gene on chromosome 5 influences the retinal expressivity because CHRPE is present only if the mutation is located between exons 9 and 15. In CHRPE-positive families, fundus examination is simple, noninvasive, reproducible, inexpensive, and allows early detection of the mutant gene carriers. Knowing the CHRPE status of patients in a family with familial adenomatous polyposis helps to identify constitutional APC mutations. The combination of genetic analysis and fundus examination offers a 100% diagnostic predictability.
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PMID:Fundus lesions of adenomatous polyposis. 1053 74

The observation that the attenuated form of adenomatous polyposis coli (AAPC) has a different mutational spectrum in both the adenomatous polyp and the carcinoma than the classical form of APC has led to the hypothesis that AAPC alleles retain some residual APC activity associated with a greatly reduced number of polyps. It is suggested that further progression to carcinoma may be dependent upon either loss of the AAPC allele (loss of heterozygosity), followed by an APC mutation in the wild-type allele, or the occurrence of APC mutations within both the AAPC and wild-type alleles.
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PMID:Colon polyps: a damaged developmental system and a precursor to cancer. 1054 97

Inherited mutations of the APC gene predispose carriers to multiple adenomatous polyps of the colon and rectum and to colorectal cancer. Mutations located at the extreme 5' end of the APC gene, however, are associated with a less severe disease known as attenuated adenomatous polyposis coli (AAPC). Many individuals with AAPC develop relatively few colorectal polyps but are still at high risk for colorectal cancer. We report here the identification of a 5' APC germline mutation in five separately ascertained AAPC families from Newfoundland, Canada. This disease-causing mutation is a single basepair change (G to A) in the splice-acceptor region of APC intron 3 that creates a mutant RNA without exon 4 of APC. The observation of the same APC mutation in five families from the same geographic area demonstrates a founder effect. Furthermore, the identification of this germline mutation strengthens the correlation between the 5' location of an APC disease-causing mutation and the attenuated polyposis phenotype.
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PMID:The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect. 1059 3

The wnt signal transduction pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of its components. The cytoplasmic component beta-catenin is central to the transmission of wnt signals to the nucleus: in the absence of wnts beta-catenin is constitutively degraded in proteasomes, whereas in the presence of wnts beta-catenin is stabilized and associates with HMG box transcription factors of the LEF/TCF family. In tumors, beta-catenin degradation is blocked by mutations of the tumor suppressor gene APC (adenomatous polyposis coli), or of beta-catenin itself. As a consequence, constitutive TCF/beta-catenin complexes are formed and activate oncogenic target genes. This review discusses the mechanisms that silence the pathway in cells that do not receive a wnt signal and goes on to describe the regulatory steps involved in the activation of the pathway.
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PMID:Biochemical interactions in the wnt pathway. 1065 74

The Wnt signaling pathway is essential for development and organogenesis. Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCC5 tend to show accumulation of beta-catenin more often than mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated beta-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers.
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PMID:AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. 1070 Jan 76

Desmoid tumors arise sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis (FAP). In FAP, two distinct clinical presentations of the desmoid phenotype are seen: 1) one or a few desmoid tumors present predominantly in the abdominal wall or the abdomen; 2) a florid proliferation of tumors early in life, mostly near the axial skeleton or extremities. These different phenotypes have been associated with different sites of germline mutations in the adenomatous polyposis coli gene (APC gene). We present a large, French-Canadian kindred with a florid desmoid tumor phenotype caused by a germline mutation at codon 2643-2644 of the APC gene. The phenotype was characterized by the early onset of multiple tumors, arising near the axial skeleton and in proximal extremities. The penetrance of desmoid tumors was near 100% in this kindred. However, the expression of the disease was variable amongst the different affected relatives. Many gene carriers had cutaneous cysts. Polyposis of the colon was rarely observed in the affected individuals and we did not document upper gastro-intestinal polyps. The mutant APC allele did not express a stable truncated protein in vivo. Molecular analysis of the proband's tumor DNA revealed a somatic inactivating mutation of the wild-type allele. Immunohistochemistry on the tumor also demonstrated elevated levels of beta-catenin. The present study demonstrates that this extreme 3' APC mutation is associated with a severely penetrant desmoid phenotype and attenuated polyposis coli. It also suggests the involvement of the beta-catenin pathway in the development of desmoid tumors in FAP. The natural history of the disease is variable between individuals, and surgical interventions have to be timed appropriately due to the frequent recurrences.
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PMID:A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. 1078 27

Membrane-associated guanylate kinases (MAGUKs) are known to function as scaffolds for forming multiprotein complexes at the synaptic junctions of neuronal cells and at sites of epithelial cell-cell contact. In Drosophila, mutations of the lethal (1)-discs large (dlg) gene, which encodes a MAGUK protein, leads to post-synaptic structure defects in neuronal cells and neoplastic overgrowth of epithelial cells. We previously showed that NE-dlg (neuronal and endocrine dlg), a human homolog of the dlg, plays a crucial role in formation of synaptic structure in human neuronal cells. Here we demonstrate that NE-dlg, similar to Drosophila dlg, is involved in regulation of cell cycle progression and adhesive ability of non-neuronal cells. Overexpression of NE-dlg in proliferating cells including various cancer cell lines induced growth suppression and impairment of cell adhesive ability. Furthermore, NE-dlg overexpression caused the down-regulation of beta-catenin in cancer cells regardless of mutations in the APC (adenomatous polyposis coli) gene. The PDZ domains of NE-dlg were found to be essential for the growth suppression, loss of adhesive property and down-regulation of beta-catenin. We propose that NE-dlg regulates the cell growth and adhesive ability by controlling the level of beta-catenin through an APC-independent pathway. Inactivation of NE-dlg may therefore contribute to development and/or progression of human neoplasms.
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PMID:NE-dlg, a mammalian homolog of Drosophila dlg tumor suppressor, induces growth suppression and impairment of cell adhesion: possible involvement of down-regulation of beta-catenin by NE-dlg expression. 1079 59

The multiple intestinal neoplasia (Apc(Min/+)) mouse possesses a germline mutation at codon 850 of the adenomatous polyposis coli (Apc) gene resulting in the formation of a nonfunctional truncated gene product. Following a somatic mutation of the remaining wild-type allele, mice spontaneously develop approximately 40-50 tumors throughout the intestinal tract. This mouse model has been used to study intestinal tumorigenesis because this mutation is analogous to the inherited APC mutation in humans with familial adenomatous polyposis (FAP). These individuals characteristically develop numerous adenomas throughout their intestinal tracts. Only a few studies have evaluated the effects of dietary fatty acids on tumorigenesis in this animal model with varying results, and none have linked these effects to alterations in arachidonic acid (AA) metabolism. This study was designed to evaluate the antitumorigenic effect of dietary (n-3) polyunsaturated fatty acids (PUFA) in the Apc(Min/+) mouse model and to determine whether these effects are related to inhibition of AA metabolism. Male Apc(Min/+)mice were fed diets supplemented with eicosapentaenoic acid (EPA), AA or a combination of AA + EPA. Mean tumor number in the EPA group was 68% lower (P<0.05) compared with the control group, whereas AA supplementation did not significantly alter tumor load. The reduction in tumor load coincided with significant reductions in intestinal AA content and levels of prostaglandins. However, supplementing AA to the EPA diet (AA + EPA) abolished the antitumorigenic effect of EPA, increased tissue AA content fourfold and prostaglandin production two- to fourfold. These results indicate that AA is involved in tumorigenesis and suggest that EPA's ability to reduce tumor load in Apc(Min/+) mice is related to reductions in tissue AA content or its metabolism.
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PMID:Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice. 1080 12

The Wnt/APC (adenomatous polyposis coli)/beta-catenin pathway plays a central role in the pathogenesis of colorectal cancer and probably also in normal development of the gastrointestinal tract. Frizzled proteins function as cell-surface receptors for the Wnt family of extracellular ligands. Many components of the Wnt signalling pathway are expressed widely, and determinants of tissue-specific functions are poorly understood. A better understanding of how Wnt signalling regulates tissue-specific development and gut epithelial homoeostasis requires characterization of the many components of this signalling pathway. We therefore wished to identify frizzled genes with limited tissue distribution of expression and isolated Mfz10, a novel member of the mouse family of frizzled genes, from the developing fetal gut. Highest levels of Mfz10 mRNA are detected throughout late embryonic development, in the brain, heart, lung and digestive tract. In adult mice Mfz10 mRNA is detected at highest levels in the heart, brain and lung. Expression in the adult gastrointestinal tract is much weaker, with higher levels in foregut derivatives (oesophagus and stomach) compared with regions derived from the fetal midgut and hindgut; particularly strong mRNA expression is observed in the squamous epithelium of the oesophagus. The amino acid sequence of Mfz10 is nearly identical to that of human FzE2 (also known as FzD2). Interestingly, mRNA levels of human FzD2 are reported to be up-regulated in oesophageal squamous cell carcinomas. These findings suggest a likely role for Mfz10 in the developing and adult foregut.
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PMID:Structure and expression of a novel frizzled gene isolated from the developing mouse gut. 1090 45


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