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 spectrum of disease causing mutations is immense. It just so happens that the overwhelming majority of genetic alterations in the APC gene with leads to adenomatous polyposis coli generate truncated gene products. This observation lead to the development of the in vitro synthesis protein assay (protein truncation test) which is a sensitive method to detect these truncated gene products from patient samples. This article describes the assay to detect truncated proteins for the APC gene, which can also be applied to other disease causing genetic alterations which commonly lead to truncations such in HNPCC, von Hippel-Lindau, osteogenesis imperfecta, retinoblastoma, BCRAI, beta-thalassemia, hemophilia B, Duchenene and Becker muscular dystrophy.
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PMID:Direct analysis for familial adenomatous polyposis mutations. 1187 75

Colorectal cancer (CRC) is the second most common fatal malignancy in the Western world, with more than 150,000 new cases accounting for 55,000 deaths in the United States every year. Surgical resection is an effective treatment for localized disease, achieving a 5-year survival rate of 90%; but chemotherapy and other novel treatments for metastatic disease remain ineffective. There have been significant efforts to identify risk factors associated with the development of CRC and to explore potential preventive therapies. Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of CRC. Cooperative genetic aberrations involving APC (adenomatous polyposis coli), beta-catenine, K-ras, and p53 are involved in the multistep adenoma-carcinoma sequence of CRC. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of colorectal carcinoma. Several reports indicate a close relation between the intake of nonsteroidal antiinflammatory drugs (NSAIDs) and a decreased risk for developing colorectal cancer. Epidemiologic studies indicate a 40% to 50% reduction in mortality due to colorectal cancer in individuals taking NSAIDs (e.g., aspirin). Epigenetic factors including age, diet, angiogenesis, and immune responses also appear to contribute to the development of CRC. Combining knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of CRC. These developments may yield benefits in earlier detection and in the design of better antitumor interventions.
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PMID:New strategies for colorectal cancer prevention and treatment. 1194 69

Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5' mutations produce APC protein that down-regulates beta-catenin, inhibits beta-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG 184 permits internal ribosome entry in a bicistronic vector. These data suggest that AAPC alleles in vivo may produce functional APC by internal initiation and establish a functional correlation between 5' APC mutations and their associated clinical phenotype.
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PMID:Attenuated APC alleles produce functional protein from internal translation initiation. 1203 71

According to the classical interpretation of Knudson's 'two-hit' hypothesis for tumorigenesis, the two 'hits' are independent mutation events, the end result of which is loss of a tumor suppressing function. Recently, it has been shown that the APC (adenomatous polyposis coli) gene does not entirely follow this model. Both the position and type of the second hit in familial adenomatous polyposis (FAP) polyps depend on the localization of the germline mutation. This non-random distribution of somatic hits has been interpreted as the result of selection for more advantageous mutations during tumor formation. However, the APC gene encodes for a multifunctional protein, and the exact cellular function upon which this selection is based is yet unknown. In this study, we have analyzed somatic APC point mutations and loss of heterozygosity (LOH) in 133 colorectal adenomas from six FAP patients. We observed that when germline mutations result in truncated proteins without any of the seven beta-catenin downregulating 20-amino-acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retain one or, less frequently, two of the same 20-amino-acid repeats. Conversely, when the germline mutation results in a truncated protein retaining one 20-amino-acid repeat, most second hits remove all 20-amino-acid repeats. The latter is frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retains two such repeats, the majority of the somatic hits are point mutations (and not LOH) located upstream and removing all of the 20-amino-acid repeats. These results indicate selection for APC genotypes that are likely to retain some activity in downregulating beta-catenin signaling. We propose that this selection process is aimed at a specific degree of beta-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the beta-catenin downregulating motifs in APC.
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PMID:The 'just-right' signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. 1204 8

The first aim of this study is to assess the frequency of osteomatous jaw lesions in patients with a diagnosis of familial adenomatous polyposis (FAP), and a group of FAP-relatives from the FAP registry of Majorca (Balearic Islands, Spain). The second aim is to study the predictive significance of osteomatous jaw lesions in families with FAP. The study included forty-two people. Twenty-five patients and seventeen relatives. All individuals underwent pantomography. Osteomatous jaw lesions were diagnosed in 68% of FAP-patients, and 6% of FAP-relatives. The difference was statistically significant (p < 0.001). The sensitivity was 68%, the specificity 94% and positive predictive value 94%. This frequency of osteomatous jaw lesions agree with previous studies of FAP-patients (57-82%), but differ from these of the previous studies of FAP-relatives (16-18%). The available method detect APC (adenomatous polyposis coli) gene mutations in 48-82% of FAP families. In the families without detected mutation, non-informative study or non-available study, the screening is based in seriated sigmoidoscopy and study of the extraintestinals lesions of the FAP syndrome. The frequency of osteomatous jaw lesions in FAP-patients is greater than the observed in FAP-relatives (p < 0.001). Osteomas in families with FAP are of predictive significance.
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PMID:[Osteomatous jaw lesions in familial adenomatous polyposis]. 1206

The APC (adenomatous polyposis coli) tumor suppressor protein has many different intracellular functions including a nuclear export activity. Only little is known about the molecular architecture of the 2843-amino acid APC protein. Guided by secondary structure predictions we identified a fragment close to the N-terminal end, termed APC-(129-250), as a soluble and protease-resistant domain. We solved the crystal structure of APC-(129-250), which is monomeric and consists of three alpha-helices forming two separate antiparallel coiled coils. APC-(129-250) includes the nuclear export signal NES-(165-174) at the C-terminal end of the first helix. Surprisingly, the conserved hydrophobic amino acids of NES-(165-174) are buried in one of the coiled coils and are thus not accessible for interaction with other proteins. We demonstrate the direct interaction of APC-(129-250) with the nuclear export factor chromosome maintenance region 1 (Crm-1). This interaction is enhanced by the small GTPase Ran in its activated GTP-bound form and also by a double mutation in APC-(129-250), which deletes two amino acids forming two of the major interhelical interactions within the coiled coil. These observations hint to a regulatory mechanism of the APC nuclear export activity by NES masking.
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PMID:The coiled coil region (amino acids 129-250) of the tumor suppressor protein adenomatous polyposis coli (APC). Its structure and its interaction with chromosome maintenance region 1 (Crm-1). 1207 Jan 64

Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.
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PMID:Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. 1212 4

Germline mutations of the adenomatous polyposis coli ( APC) gene cause familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease that predisposes patients to colorectal cancer. The APC gene is composed of 15 coding exons and encodes an open reading frame of 8.5 kb. The 3' 6.5 kb of the APCopen reading frame is encoded by a single exon, exon 15. Most identified APC mutations are at the 5' half of the APC open reading frame and are nucleotide substitutions and small deletions or insertions that result in truncation of the APC protein. Very few well-characterized gross alterations of APC have been reported. Patients with FAP typically develop hundreds to thousands of colorectal tumors beginning in their adolescence. A subgroup of patients with FAP who develop fewer tumors at an older age have what is called attenuated FAP (AFAP). Accumulating evidence indicates that patients carrying germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9, or in the 3' half of the coding region usually develop AFAP. We characterized two germline APC alterations that deleted the entire APC exon 15 as the result of 56-kb and 73-kb deletions at the APC locus. A surprising finding was that one proband had the typical FAP phenotype, whereas the other had a phenotype consistent with that of AFAP.
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PMID:Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15. 1213 40

Thrombospondin 1 (TSP-1) is a multifunctional extracellular matrix protein that is an endogenous regulator of tumor angiogenesis. The effects of TSP-1 on adenoma formation and development into cancerous lesions has been evaluated in the Min(/+) (multiple intestinal neoplasia) mouse model. These mice develop multiple adenomas in the small intestine due to a mutation in the homologous APC (adenomatous polyposis coli) gene. As in its human counterpart, these adenomas may progress to carcinomas. Intestines of APC(Min/+) mice were dissected and histologic evaluation of adenomas was then conducted. Significant increases in vascularization and proliferation were observed in adenomatous, as compared with normal, mucosa. TSP-1 immunostaining revealed significant decreases in the number and intensity of positive cells in adenomas, as compared with normal mucosa. TSP-1 scores were inversely correlated with vascularity and proliferation rate. Cross breeding of mice homozygous for a deletion of the TSP-1 gene (TSP-1(-/-)) with mice heterozygous for the APC gene mutation (APC(Min/+)), resulted in animals that showed a significant increase in adenoma number and diameter. Also, histopathological examination of these adenomas showed accelerated dysplasic changes, carcinoma in situ and early invasion, compared with their APC(Min/+) littermates. Moreover, a significant decrease of TUNEL-positive cells was observed in intestinal adenomas of TSP-1(-/-)/APC(Min/+) mice. This study reports the first in vivo impact of TSP-1 during early stages of tumor initiation and development in an intestinal carcinogenesis model and demonstrates that TSP-1 affects both angiogenesis and tumor cell apoptosis.
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PMID:Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model. 1258 68

The Wnt signaling pathway plays critical roles in the embryonic development and tumorigenesis. As a part of the Wnt signal transduction, the function of Axin complex is inhibited, leading to accumulation of beta-catenin. In hepatoblastomas, loss of APC (adenomatous polyposis coli) function or activation of beta-catenin that are the other two components involving in Wnt signaling has been demonstrated. Because hepatoblastoma shows immunohistochemical positivity of beta-catenin more often than its mutation frequency, we analyzed the Axin gene as a candidate to lead beta-catenin accumulation in hepatoblastoma. The coding region of the Axin gene was examined by PCR-SSCP using 24 sets of the primers in 22 hepatoblastomas and some paired normal tissues. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. We identified totally eight variants in the exons and four intronic nucleotide substitutions. Seven variants in the exons were silent mutations, however, the remaining variant at codon 95 (ACG-->ATG) found in one hepatoblastoma predicted to result in an amino acid change from threonine to methionine. The paired peripheral blood DNAs from this patient also showed the same change; we suggested that it was a germline mutation of Axin gene. Our results suggest that mutation of the Axin gene may have a tumorigenic function in a subset of childhood hepatoblastomas.
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PMID:Sequence variants of the Axin gene in hepatoblastoma. 1264 54


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