Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between the grade of astrocytic tumor and the expression of deoxyribonucleic acid methyltransferase (DNA-MTase) gene was examined. The levels of DNA-MTase messenger ribonucleic acid (mRNA) were measured by semiquantitative reverse transcriptase-polymerase chain reaction in surgical specimens from 12 astrocytic tumors (4 astrocytomas, 6 anaplastic astrocytomas, and 2 glioblastomas) and two normal brain tissues, and in four glioma cell lines. Compared to normal brain tissues, the levels of DNA-MTase mRNA were increased by 16- to 55-fold in low grade astrocytomas, and significantly increased by 200- to 4500-fold in high grade astrocytomas (anaplastic astrocytomas and glioblastomas) and more than 4500-fold in glioma cell lines. In situ hybridization with paraffin-embedded surgical specimens of human astrocytic tumors showed DNA-MTase mRNA was abundantly expressed in high grade astrocytomas. The detection of increased DNA-MTase expression in astrocytic tumor indicates involvement in the tumorigenesis and suggests that blocking of this change with specific inhibitors may offer new therapeutic strategies for malignant astrocytic tumors.
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PMID:Increased expression of deoxyribonucleic acid methyltransferase gene in human astrocytic tumors. 1110 93

Aberrant genome-wide hypomethylation has been thought to be related to tumorigenesis. However, its mechanism and implications in hepatocellular carcinogenesis remain to be elucidated. Samples of hepatoma (hepatocellular carcinoma, HCC) and paired non-HCC liver tissues were obtained from 17 HCC patients. Normal liver tissues obtained from three individuals were used as controls. Compared with the paired non-HCC liver tissues, genome-wide 5-methylcytosine content in HCC was reduced in all of the tested HCC samples (P < 0.001). Conversely, genome-wide 5-methylcytosine content did not significantly differ among normal, noncirrhotic, and cirrhotic liver tissues. Moreover, the degree of reduced DNA methylation was related to late histopathological HCC grade (P = 0.005) and large tumor size (P = 0.079). Compared with the paired non-HCC liver tissues, expression of DNA methyltransferases DNMT-1, DNMT-3A, and DNMT-3B and the DNA methyltransferase-like gene, DNMT-2, was up-regulated in 53, 41, 59, and 47% of the HCC samples, respectively. Surprisingly, small amounts of LINE-1 retrotransposon transcripts were detected in HCC and non-HCC as well as normal liver tissues, and the expression levels were not significantly different in HCC compared with the paired non-HCC or normal liver tissues. Of interest, the 3' ends of these LINE-1 transcripts were truncated. Our findings suggest that genome-wide hypomethylation in HCC is a continuing process that persists throughout the lifetime of the tumor cells rather than a historical event occurring in precancer stages or in cell origins for HCC. Up-regulation of DNA methyltransferases might simply be a result of increased cell proliferation in cancer. In addition, our results did not support the hypothesis of activation of transposable elements in HCC via genome-wide hypomethylation.
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PMID:Genome-wide hypomethylation in hepatocellular carcinogenesis. 1135 50

Tumor suppressor gene inactivation is a crucial event in oncogenesis. Gene inactivation mechanisms include events resulting in loss of heterozygosity (LOH), gene mutation, and transcriptional silencing. The contribution of each of these different pathways varies among tumor suppressor genes and by cancer type. The factors that influence the relative utilization of gene inactivation pathways are poorly understood. In this study, we describe a detailed quantitative analysis of the three major gene inactivation mechanisms for a model gene at two different genomic integration sites in mouse embryonic stem (ES) cells. In addition, we targeted the major DNA methyltransferase gene, Dnmt1, to investigate the relative contribution of DNA methylation to these various competing gene inactivation pathways. Our data show that gene loss is the predominant mode of inactivation of a herpes simplex virus thymidine kinase neomycin phosphotransferase reporter gene (HSV-TKNeo) at the two integration sites tested and that this event is significantly reduced in Dnmt1-deficient cells. Gene silencing by promoter methylation requires Dnmt1, suggesting that the expression of Dnmt3a and Dnmt3b alone in ES cells is insufficient to achieve effective gene silencing. We used a novel assay to show that missense mutation rates are also substantially reduced in Dnmt1-deficient cells. This is the first direct demonstration that DNA methylation affects point mutation rates in mammalian cells. Surprisingly, the fraction of CpG transition mutations was not reduced in Dnmt1-deficient cells. Finally, we show that methyl group-deficient growth conditions do not cause an increase in missense mutation rates in Dnmt1-proficient cells, as predicted by methyltransferase-mediated mutagenesis models. We conclude that Dnmt1 deficiency and the accompanying genomic DNA hypomethylation result in a reduction of three major pathways of gene inactivation in our model system.
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PMID:Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells. 1160 95

Inactivation of nuclear retinoic acid receptor beta (RARbeta) expression is implicated in tumorigenesis. We hypothesized that loss of RARbeta in gastric cancer cells may occur as a result of multiple factors, including epigenetic modifications which alter RARbeta promoter chromatin structure. We examined hypermethylation of CpG islands present in the RARbeta promoter by methylation-specific PCR and the expression of RARbeta in gastric cancer cell lines and tissues. Three (MKN-28, -45 and -74) out of eight gastric cancer cell lines had a loss of RAR expression associated with promoter methylation. RARbeta expression was retrieved in these cell lines by treatment with 5-azacytidine or by the histone deacetylase inhibitor trichostatin A. Promoter hypermethylation was detected in 64% (7/11) of gastric carcinoma tissues with reduced expression of RARbeta, whereas it was detected in 22% (2/9) of tumors with retained RARbeta expression. To investigate the functions of exogenous RARbeta in gastric cancer cells, we transfected a retroviral RARbeta expression vector (LNSbeta) into MKN-28 cells that have hypermethylation of the RARbeta promoter. Overexpression of RAR in MKN-28 cells appeared to regulate the expression of DNA methyltransferase and DNA demethylase and the acetylation of hitone H4. These results suggest that the transcriptional inactivation of the RARbeta by promoter CpG hypermethylation is frequently associated with gastric carcinoma. Our data also suggests that DNA methylation plays a pivotal role in establishing and maintaining an inactive state of RARbeta by rendering the chromatin structure inaccessible to the transcription machinery.
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PMID:Inactivation of retinoic acid receptor beta by promoter CpG hypermethylation in gastric cancer. 1168 89

Promoter CpG island hypermethylation of critical genes is thought to play an important role in human colorectal tumorigenesis. In this study, we show that low levels of CpG island methylation occur in the normal intestinal mucosa of Apc(Min/+) mice and are increased in Multiple Intestinal Metaplasia (Min) polyps. We examined the interaction between CpG island hypermethylation and tumorigenesis by genetically modulating expression levels of the predominant DNA methyltransferase, Dnmt1, in Apc(Min/+) mice. We show that a combination of Dnmt1 hypomorphic alleles results in the complete suppression of polyp formation and an accompanying reduction in the frequency of CpG island methylation in both the normal intestinal mucosa and intestinal adenomas. These results suggest that sufficient DNA methyltransferase expression is a prerequisite for polyp formation and that hypomorphic alleles of Dnmt1 are not merely genetic modifiers but the first identified true genetic suppressors of the Min phenotype.
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PMID:Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. 1188 94

The regulation of gene transcription is not simply dependent on the presence or absence of DNA-binding transcription factors that turn genes on or off, but also involves processes determining the ability of transcription factors to gain access to and bind their target DNA. Methylation of DNA cytosine bases leads to the inaccessibility of DNA regulatory elements to their transcription factors by a number of mechanisms. Our understanding of DNA methylation has advanced rapidly in recent years with the identification of an increasingly large number of novel proteins involved in this process. These include methylcytosine-binding proteins as well as additional members of the DNA methyltransferase family. The creation of mice with targeted deletions in a number of genes involved in DNA methylation has further elucidated the functions of many of these proteins. The characterization of complexes that contain proteins known to be involved in DNA methylation has led to the identification of additional proteins, especially those involved in histone deacetylation, indicating that DNA methylation and histone deacetylation very likely act in a synergistic fashion to regulate gene transcription. Finally, the implication of DNA methylation in tumorigenesis and the realization that some congenital diseases are caused by deficiency of proteins involved in DNA methylation has confirmed the importance of this process in regulating gene expression.
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PMID:DNA methylation and the regulation of gene transcription. 1191 42

DNA methylation alterations are now widely recognized as a contributing factor in human tumorigenesis. A significant number of tumor suppressor genes are transcriptionally silenced by promoter hypermethylation, and recent research implicates alterations in chromatin structure as the mechanistic basis for this repression. The enzymes responsible for catalyzing DNA-cytosine methylation, as well as the proteins involved in interpreting the DNA methylation signal, have now been elucidated. Technological advances, including gene expression microarrays and genome scanning techniques, have allowed the comprehensive measurement of DNA methylation changes in human cancers. An important distinction between DNA methylation (epigenetic) and mutation or deletion (genetic) tumor suppressor gene inactivation is that epigenetic inactivation can be abrogated by small molecules, including DNA methyltransferase and histone deacetylase inhibitors. Further, strategies have been developed that combine treatments with drugs that reactivate silenced gene expression with secondary agents that target the re-expressed genes and/or reconstituted signal transduction pathways. In this review, we will discuss in detail the mechanisms of gene silencing by DNA methylation, the techniques used to decipher the complement of methylation-inactivated genes in human cancers, and current and future strategies for reactivating the expression of methylation-silenced genes.
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PMID:Reactivating the expression of methylation silenced genes in human cancer. 1215 10

DNA methylation regulates important biological processes and is involved in tumorigenesis and several human diseases, such as Rett and immunodeficiency, centromeric instability and facial anomalies (ICF). The major objective of our research is to investigate the roles of DNA methylation in mammals through genetic analysis of DNA methyltransferase genes in mouse and human. Previously, we found that Dnmt1 knockout embryonic stem (ES) cells are capable of methylating retroviral DNA de novo. In search of enzymes responsible for de novo methylation, we have cloned a novel family of mammalian DNA methyltransferase genes, Dnmt3a and Dnmt3b. Although extensive sequence similarity was found between Dnmt3a and Dnmt3b, little homology was observed between Dnmt1 and Dnmt3a/3b in the catalytic domain as well as in the N-terminal domain. Additionally, biochemical analysis revealed that, unlike Dnmt1, neither Dnmt3a nor Dnmt3b had a strong preference to hemimethylated DNA substrates. Genetic analysis demonstrated that Dnmt3a and Dnmt3b were required for de novo methylation activities in ES cells and during early embryogenesis and were essential for early development. Interestingly, phenotype analyses of single homozygous mice for either Dnmt3a or Dnmt3b suggested that the functions of Dnmt3a and Dnmt3b also were required at the late developmental stage and even at the adult stage.
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PMID:Genetic analyses of DNA methyltransferase genes in mouse model system. 1216 12

Retinoic acid (RA) receptor (RAR) beta2 has been shown to be underexpressed in human breast cancer cells, including MCF-7 cells, and recent reports have suggested that hypermethylation of the RAR beta2 promoter and 5'-UTR is the underlying cause. Here we show that RAR alpha2 is also underexpressed in MCF-7 breast cancer cells, at both the message and the protein level, relative to normal or nontumorigenic breast epithelial cells. Bisulfite sequencing of the CpG island in the RAR alpha2 promoter revealed highly penetrant and uniform cytosine methylation in MCF-7 cells. Pretreatment with the DNA methyltransferase inhibitor, azacytidine, followed by treatment with RA and a histone deacetylase inhibitor, trichostatin A, resulted in partial promoter demethylation and RAR alpha2 induction, which strongly suggested that promoter hypermethylation is responsible for RAR alpha2 underexpression. We compared the outcome of ectopic expression in MCF-7 cells of matched levels of RAR alpha2 and RAR beta2. On the basis of a clonogenic assay, RAR alpha2 displayed ligand-dependent growth-suppressive activity similar to that of RARb eta2; thus, 10 and 20 nM RA inhibited clonogenic growth by 52 and 80%, respectively, in RAR alpha2-transfected cells compared with 75 and 77%, respectively, in RAR beta2-transfected cells. We conclude that the silencing of the RAR alpha2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis.
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PMID:Retinoic acid receptor alpha2 is a growth suppressor epigenetically silenced in MCF-7 human breast cancer cells. 1219 72

We quantitatively analysed hypermethylation at CpG islands in the 5' ends of 12 genes and one non-CpG island 5' region (MTHFR) in 31 Wilms tumors. We also determined their global genomic 5-methylcytosine content. Compared with various normal postnatal tissues, approximately 40-90% of these pediatric kidney cancers were hypermethylated in four of the genes, MCJ, RASSF1A, TNFRSF12 and CALCA as determined by a quantitative bisulfite-based assay (MethyLight). Interestingly, the non-CpG island 5' region of MTHFR was less methylated in most tumors relative to the normal tissues. By chromatographic analysis of DNA digested to deoxynucleosides, about 60% of the Wilms tumors were found to be deficient in their overall levels of DNA methylation. We also analysed expression of the three known functional DNA methyltransferase genes. No relationship was observed between global genomic 5-methylcytosine levels and relative amounts of RNA for DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. Importantly, no association was seen between CpG island hypermethylation and global DNA hypomethylation in these cancers. Therefore, the overall genomic hypomethylation frequently observed in cancers is probably not just a response or a prelude to hypermethylation elsewhere in the genome. This suggests that the DNA hypomethylation contributes independently to oncogenesis or tumor progression.
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PMID:Hypomethylation and hypermethylation of DNA in Wilms tumors. 1224 69


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