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Disease relevance of MGMT

• We have recently demonstrated that the MGMT gene is silenced by promoter methylation in many human tumors, including colorectal carcinomas [1].
• In addition, MGMT loss associated with hypermethylation was observed in the small adenomas, including those that do not yet contain K-ras mutations [1].
• These results provide the first link between germ-line functional deficits in pathways that protect the cell from tobacco- and radon-induced DNA damage, and the development of aberrant promoter methylation of the p16 and MGMT genes in the respiratory epithelium of individuals at high risk for lung cancer [2].
• Hypermethylation of the MGMT promoter was more common in adenocarcinoma than in other histological types of NSCLC and was also more common in poorly differentiated tumors [3].
• Hypermethylation of MGMT, RASSF1A, and DAPK was significantly lower in primary melanomas (n=20) compared to metastatic melanomas [4].
• We have found a strong association between the germline polymorphism (c.-56C>T) of the MGMT promoter and promoter methylation/silencing of MGMT in colorectal cancer [5].
• Even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy [6].

Psychiatry related information on MGMT

• The expression of MGMT mRNA in liver tissue was quantitatively assessed by the competitive reverse transcription-polymerase chain reaction method in patients with chronic liver diseases with or without alcohol drinking [7].
• Recent data suggest that class prediction models, based on defined molecular profiles, and assessment of MGMT promoter methylation might contribute to improved patient stratification and decision making [8].
• The relationship was examined between the outcome (i.e., presence or absence of liver tumors, and latency period) and the hepatic activities of mixed function oxidases and conjugating enzymes, as well as of O6-methylguanine-DNA-methyltransferase, measured before the carcinogen treatment [9].
• O6-methylguanine-DNA methyltransferase in lymphocytes of the elderly with and without Alzheimer's disease [10].

High impact information on MGMT

• O6-methylguanine-DNA methyltransferase directly reverses some simple alkylation adducts [11].
• The DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents [12].
• The DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents [13].
• We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents [14].

Chemical compound and disease context of MGMT

• PURPOSE: In glioblastoma multiforme (GBM), the cytotoxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolamide is dependent on O(6) alkylation, which correlates inversely with expression of the DNA repair enzyme O(6)-methyl-guanine-DNA methyltransferase (MGMT) [15].
• We have comparatively analyzed the expression of MGMT and the different base excision repair genes in rat hepatoma cells (line H4IIE) after exposure to alkylating agents, X-rays and the glucocorticoid hormone dexamethasone [16].
• Tumor promoters such as Phorbol esters (TPA) induce MGMT via protein kinase C signaling [17].
• In melanoma cells that acquired resistance to fotemustine, the amount of nuclear MMR proteins was nearly unaltered, whereas the activity of O6-methylguanine-DNA methyltransferase (MGMT) was considerably enhanced [18].
• These results indicate that the MDR1-MGMT bicistronic retrovirus vectors would be useful to protect normal hematopoietic cells from nitrosourea-induced mutagenesis, and drug-selectable bicistronic constructs would have great advantage over non-selectable vectors [19].
• However, there was no significant correlation of MMR expression alone or combined with MGMT levels with clinical response to DTIC-based chemotherapy in metastatic melanoma [20].

Biological context of MGMT

• Thus, through a change in conformation upon repair of the 6RG lesion, MGMT switches from a DNA repair factor to a transcription regulator (R-MGMT), enabling the cell to sense as well as respond to mutagens [21].
• Second, R-MGMT, which adopts an altered conformation, utilizes its exposed VLWKLLKVV peptide domain (codons 98 to 106) to bind ER [21].
• Methylation of the promoter region of the MGMT gene was determined using methylation-specific PCR and was present in 27 of 92 (29%) tumors [3].
• The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum [2].
• Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny [2].

Anatomical context of MGMT

• Methylation of the MGMT gene was seen in sputum from 9 controls, whereas RASSFIA promoter methylation was only seen in 2 controls [22].
• Furthermore, the most BCNU-sensitive cell lines were all MGMT-poor [23].
• The correlation of UV sensitivity with BCNU cytotoxicity suggests that nucleotide excision repair is an important modifying factor of MGMT-mediated innate CENU resistance in human tumor cell lines, especially in highly resistant cell lines [23].
• Murine bone marrow cells transduced with Ha-MDR-IRES-MGMT and selected with vincristine also showed simultaneous resistance to vincristine and ACNU [24].
• One vector is Ha-MDR-IRES-MGMT, in which translation of the MDR1 cDNA is cap-dependent and MGMT translation is dependent on an internal ribosome entry site (IRES) [24].

Associations of MGMT with chemical compounds

• O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from the O6 position of guanine [1].
• Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0-9.2) [2].
• These results indicate that MGMT is the primary mechanism for temozolomide resistance, but in the absence of MGMT, proficient mismatch repair determines sensitivity to this agent [25].
• Cells transduced with Ha-MDR-IRES-MGMT showed higher resistance to vincristine and lower resistance to ACNU than those transduced with Ha-MGMT-IRES-MDR [24].
• In the 16 patients treated with temozolamide plus cisplatin, no significant correlation between MGMT methylation status and response was observed, whereas in BCNU-treated patients, a significant difference was observed in favor of those with methylated MGMT [15].
• Evidence from cysteine/methionine deprivation, acivicin treatment, and protein synthesis measurements in OTC-treated cells suggested that an increased cysteine flux also contributed significantly to enhanced MGMT expression [26].
• Interestingly, combined treatment of GBM12 flank xenografts with temozolomide and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of temozolomide resistance by MGMT overexpression as compared with treatment with temozolomide alone [27].

Physical interactions of MGMT

• Furthermore, MeCP2 preferentially bound to the CpG-methylated island in the MGMT negative line [28].
• Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene [29].

Enzymatic interactions of MGMT

• EXPERIMENTAL DESIGN: MGMT hypermethylation, expressed as the ratio between methylated MGMT to unmethylated MYOD1 in genomic DNA, was analyzed in normal and matching tumor tissue from 90 patients with NSCLC, and a control group of 10 patients without cancer using a methylation-specific fluorogenic Real-Time PCR (Taqman) system [30].
• Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide [31].

Regulatory relationships of MGMT

• No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed [32].
• CONCLUSIONS: These data suggest that the Leu84Phe polymorphism affect the capacity of MGMT to inhibit estrogen receptor-mediated cell proliferation and is associated with breast cancer risk [33].
• Because, a marginal enhancement of this protein may be adequate for genomic protection, we studied alterations in MGMT activity and expression in human peripheral blood lymphocytes and cancer cell lines induced by water-soluble and alcohol-soluble constituents of several plants with established antioxidant and medicinal properties [34].
• Transgenic expression of hMGMT significantly but incompletely blocked MNU lymphomagenesis in PMS2-/- mice [35].
• To test this, we examined apoptosis triggered by O(6)MeG in human peripheral lymphocytes in which O(6)-methylguanine-DNA methyltransferase (MGMT) had been inactivated by O(6)-benzylguanine (O(6)BG) and which were not proliferating or proliferating upon CD3/CD28 stimulation [36].

Other interactions of MGMT

• From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively [37].
• The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples] [38].
• Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013) [39].
• In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A [40].
• None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs [40].

Analytical, diagnostic and therapeutic context of MGMT

• A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry [41].
• The expression levels of P-glycoprotein or MGMT in the transduced cells determined by FACS and Western blot analysis correlated well with the extent of resistance to vincristine and ACNU, respectively [24].
• Exposure of buccal cell cultures to various organic or water-based extracts of products related to the use of tobacco and betel quid, decreased both cell survival (measured by reduction of tetrazolium dye) and MGMT activity (measured subsequently to the exposures in cellular extracts) [42].
• In a previous study, we constructed two bicistronic retroviral vectors, Ha-MDR-IRES-MGMT and Ha-MGMT-IRES-MDR, that allow co-expression of the MGMT gene and the MDR1 gene to protect cells from the toxicity of combination chemotherapy [19].
• Therefore, we isolated MGMT-interacting proteins from extracts of HT29 human colon cancer cells using affinity chromatography on MGMT-Sepharose [43].

References