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)

Best's vitelliform macular dystrophy is an autosomal dominant disorder of unknown causes. To identify the underlying gene defect the disease locus has been mapped to an approximately 1.4-Mb region on chromosome 11q12-q13.1. As a prerequisite for its positional cloning we have assembled a high coverage PAC contig of the candidate region. Here, we report the construction of a primary transcript map that places a total of 19 genes within the Best's disease region. This includes 14 transcripts of as yet unknown function obtained by EST mapping and/or cDNA selection and five genes mapped previously to the interval (CD5, PGA, DDB1, FEN1, and FTH1). Northern blot analyses were performed to determine the expression profiles in various human tissues. At least three genes appear to be good candidates for Best's disease based on their abundant expression in retina or retinal pigment epithelium. Additional information on the functional properties of these genes, as well as mutation analyses in Best's disease patients, have to await their further characterization. [The GenBank/EMBL accession numbers and details of the isolation, localization, and characterization of ESTs and selected cDNAs are available as online supplements in Online Tables 1-3 at http://www.genome.org.]
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PMID:A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1. 944 87

Dietary inadequacy of folate enhances and folate supplementation suppresses colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an essential factor for DNA methylation and the de novo biosynthesis of nucleotides, aberrations of which play important roles in mutagenesis. This study investigated whether the mutational hot spots of the Apc and p53 genes for human colorectal cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether dietary folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg folate/kg diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Apc mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one adenocarcinoma. All mutations were single base substitutions, four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cluster region. Dietary folate had no effect on the frequency and type of Apc mutations. No mutations were detected in exons 5-9 of the p53 gene in neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutational hot spot of the p53 gene for human colorectal cancer is not commonly mutated. Although the low frequency of Apc mutations and the small number of neoplasms studied in this study might have precluded our ability to observe modulatory effects of folate, dietary folate appears to have no significant effect on Apc and p53 mutations.
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PMID:The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine rat model of colorectal cancer. 1059 Feb 31

Folate-sensitive fragile sites are associated with the expansion and hypermethylation of CCG-repeats. The fragile site in 11q23.3, FRA11B, has been shown to cause chromosome deletions in vivo, its expression being associated with Jacobsen (11q-) syndrome. However, the majority of Jacobsen deletions are distal to FRA11B and are not related to its expression. To test the hypothesis that other unidentified fragile sites might be located in 11q23.3-24 and may cause these deletions, we have identified and characterised CCG-trinucleotide repeats within a 40 Mb YAC contig spanning distal chromosome 11q. Only eight CCG-repeats were identified within the entire YAC contig (not including FRA11B ), six of which map to the region of 11q23.3-24 that includes Jacobsen deletions. We have previously collated the deletion mapping data of 24 Jacobsen patients with the physical map of chromosome 11q, and accurately localised six breakpoints to short intervals corresponding to individual YAC clones. We now show that in each of these cases, YAC clones found to contain a deletion breakpoint also contain a CCG-repeat. The improved analysis of one of these deletions, together with those of several new Jacobsen cases, further strengthens this association by localising five breakpoints to individual PAC clones containing CCG-repeats. These data provide strong evidence for the non-random clustering of chromosome deletion breakpoints with CCG-repeats, and suggests that they may play an important role in a common mechanism of chromosome breakage.
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PMID:Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen syndrome: evidence for a common mechanism of chromosome breakage. 1076 45

Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot analysis of a 40-Mb YAC and PAC contig spanning 11q22-qter. Deletion breakpoints in CLL are found to co-localize at specific sites on 11q where CCG repeats are located. In addition, a CCG repeat has been identified within the minimal region of deletion. Specific alleles of this repeat are associated with worse prognosis. Folate-sensitive fragile sites are regions of late replication and are characterized by CCG repeats. The mechanism for chromosome deletion at 11q could be explained by a delay in replication. Described here is an association between CCG repeats and chromosome loss suggesting that in vivo "fragile sites" exist on 11q and that the instability of CCG repeats may play an important role in the pathogenesis of CLL.
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PMID:Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia. 1115 30

In many GL-7ACA acylases, the first Ser residue at the N-terminal of beta-subunit is the catalytic center. In order to investigate relationship between the N-terminal structure and catalytic activities, peptide replacement and site-directed mutagenesis were performed at the N-terminal of beta-subunit of GL-7ACA acylase C130. When the N-terminal 8 amino acid residues of C130 were replaced by the corresponding sequence of penicillin acylases PAC and PGA, respectively, the first mutant B8PAC lost the activity of the acylase, and the second mutant B8PGA had lower activity with the K(m) value increasing from 0.44x10(-3)mol.L(-1) to 0.55x10(-3) mol.L(-1), and the k(cat) decreasing from 4.92 s(-1) to 1.64 s(-1). Although the substitution of Trp (beta4) by Tyr did not change the K(m) value, the k (cat) decreased to 2.29 s(-1). When the Trp was substitued by Leu, both the K ( m ) and k ( cat ) values decreased. Compared with the wild type, mutations of Ser (beta3) to Met, Ala and Cys caused decrease of K(m) values by 52.27%, 43.18% and 38.64%, respectively. Mutation of Asn (beta2) to Gln caused the K ( m ) value being increased by 5-fold, and k ( cat ) decreased by 10-fold. These results suggested that the N-terminal amino acid residues of beta-subunit in GL-7ACA acylase C130 are important for enzyme function.
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PMID:Mutagenesis of N-terminal Amino Acid Residues in beta-subunit of Glutaryl-7-amino-cephalosporanic Acid Acylase C130. 1203 60

Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32-34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor 1 was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and beta-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7-8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk.
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PMID:Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. 1768 72

Aberrant DNA methylation is a commonly observed epigenetic change in lung cancer. Folate has been suggested to play a role in the homeostasis of DNA methylation and has also been implicated in cancer chemotherapy. We investigated a possible role for folate in DNA methylation by measuring folate concentrations in tumors and adjacent normal tissues from 72 non-small cell lung cancer (NSCLC) patients. These were compared to DNA methylation levels and to clinicopathological features. Folate concentrations were determined as the sum of 5,10-methylenetetrahydrofolate and tetrahydrofolate. The MethyLight assay was used to quantitate methylation in promoter regions of P16(CDKN2A), APC, CDH13, RARB, RASSF1, RUNX3, and MYOD1. Methylation of LINE-1 repeats was used as a surrogate for global methylation. Folate levels in tumors correlated positively with LINE-1, CDH13, and RUNX3 methylation. Folate concentrations and methylation of LINE-1, RASSF1, and RUNX3 were significantly higher in adenocarcinoma compared to squamous cell carcinoma (SCC). Two sets of array-based data retrieved from the Gene Expression Omnibus consistently showed that expression of FOLR1, a folate transport enzyme, and GGH, an enzyme that prevents folate retention, were higher and lower, respectively, in adenocarcinomas compared to SCC. This was independently validated by quantitative RT-PCR in 26 adenocarcinomas and 13 SCC. Our results suggest that folate metabolism plays a role in aberrant DNA methylation in NSCLC. The histological subtype differences in folate concentration and DNA methylation observed here were associated with distinct expression patterns for folate metabolizing enzymes. These findings may have clinical applications for histology-directed chemotherapy with fluoropyrimidine and anti-folates in NSCLC.
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PMID:Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels. 1976 99

Folate, one of the most studied dietary compounds, has recently become the main topic of debates on food fortification. Although low folate levels may be associated with increased risk of cancer development, simultaneously several reports indicate a detrimental effects mediated by high folate concentrations. Using the methylation sensitive restriction analysis (MSRA) and real-time RT-PCR we tested the effect of folic acid on DNA promoter methylation and expression of PTEN, APC and RARbeta2 tumour suppressor genes in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive capacity. The tested genes encode proteins involved in regulation of oncogenic intracellular signaling pathways. The results show that the increasing concentrations of folic acid lead to a dose-dependent down-regulation of tumour suppressor genes which may be linked to the increased DNA methylation detected within their promoter regions. The effects were more remarkable in non-invasive MCF-7 cells where we also observed 30% up-regulation of DNMT1 expression at the highest folate concentration used. Our findings show that caution need to be used when introducing folic acid supplementation since it may lead to cancer progression.
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PMID:Folic acid enforces DNA methylation-mediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer. 2321 37