Disease relevance of Mgmt

• Treatment of rat hepatoma cells (H4 cells) with various DNA-damaging agents increases the number of O6-methylguanine-DNA-methyltransferase (transferase) molecules per cell [1].
• The amount of the renal O6-methylguanine-DNA methyltransferase was increased up to 2.5-fold during renal hypertrophy in response to unilateral nephrectomy or treatment with folic acid [2].
• Modulation of nitrosourea toxicity in rodent embryonic cells by O6-benzylguanine, a depletor of O6-methylguanine-DNA methyltransferase [3].
• Adenoviral transfer of antisenses or ribozyme to O6-methylguanine-DNA methyltransferase mRNA in brain-tumor model resistant to chloroethyl-nitrosourea [4].
• The 9L rat gliosarcoma cells were retrovirally transduced with MGMT cDNA and stereotactically implanted into the brain parenchyma [5].

High impact information on Mgmt

• In mammary epithelia (very low expression of O6-alkylguanine-DNA alkyltransferase, MGMT), O6-methylguanine (O6-MeGua) was eliminated from transcribed (H-ras and beta-actin) and inactive genes (IgE heavy chain) at the same slow rate as determined for bulk genomic DNA [6].
• Contrary to the 208F wild-type cells, all variants expressed O6-methylguanine-DNA methyltransferase activity, while both kinds of cells were deficient for repair of the DNA ethylation products O2- and O4-ethylthymine [7].
• Astrocytes, O-2A progenitors, and oligodendrocytes each displayed a unique pattern of expression of six drug resistance genes: MGMT, GST mu, GST pi,p53, MDR, and MT [8].
• Furthermore, O6-methylguanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor mRNA levels were quantified [9].
• The increased resistance of astrocytes in comparison to oligodendrocytes was modulated, at least in part, by both O6-benzylguanine (BG) and DL-buthionine-(S,R)-sulfoximine, suggesting a role for both MGMT and glutathione in the resistance of astrocytes to BCNU [8].

Chemical compound and disease context of Mgmt

• The O6-methylguanine-DNA-methyltransferase (methyltransferase) activity was determined in a rat hepatoma cell line after treatment with ultraviolet or gamma-irradiation, heat treatment, or incubation with cis-diamminedichloroplatinum(II),2-methyl-9-hydroxyellipticinium, or bleomycin [10].
• O6-Methylguanine-DNA methyltransferase activity, i.e., the capacity of cells to transfer the methyl group from O6-methylguanine in DNA to protein, was determined in 10 hepatoma cell lines, all derived from Reuber H35 hepatoma but differing in their status of differentiation [11].
• The O6-methylguanine-DNA-methyltransferase activity was measured in rat hepatoma cells (H4 cells) at different times after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylmethane sulfonate (MMS) or ethylmethane sulfonate (EMS) treatment [12].
• Micromass culture systems of mesencephalon (CNS) and limb bud (LB) regions were used to evaluate the impact of the O6-methylguanine-DNA methyltransferase (MGMT) inhibitor, O6-benzylguanine (BG), on ethylnitrosourea (ENU) and methylnitrosourea (MNU)-induced in vitro toxicity [3].
• The toxicity and mutagenicity (including the mutation spectrum induced) of dacarbazine, a methylating cytostatic drug, was examined in CHO cells expressing different levels of the repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) [13].

Biological context of Mgmt

• cDNA for O6-methylguanine-DNA methyltransferase was isolated by screening rat liver cDNA libraries, using as a probe the human cDNA sequence for methyltransferase [14].
• Extracts of BK2210 cells hosting the RMGMT plasmid expressed a O6-methylguanine-DNA-methyltransferase (transferase) activity and this protein had the same molecular weight as the transferase from H4 cells [15].
• O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which plays an important role in chemotherapy, mutagenesis, and carcinogenesis [16].
• Dose response for DNA alkylation, [3H]thymidine uptake into DNA, and O6-methylguanine-DNA methyltransferase activity in hepatocytes of rats and mice continuously exposed to dimethylnitrosamine [17].
• The sensitivity of O-2A progenitors to BCNU following BG pretreatment is virtually indistinguishable from that of oligodendrocytes depleted of MGMT, suggesting that the down-regulation of MGMT is sufficient to account for the increased sensitivity of oligodendrocyte lineage cells to BCNU as they differentiate [8].

Anatomical context of Mgmt

• In contrast, the decline in O6mGua in hepatocytes was attributed to the induction of O6-methylguanine-DNA methyltransferase activity, since an 18-fold reduction in the ratio of O6mGua:7-methylguanine was observed over the 12 days of treatment [18].
• The decrease in O6mGua levels in nasal mucosa paralleled a decline in O6-methylguanine-DNA methyltransferase activity and was associated with marked cytotoxicity to Bowman's glands, portions of the lateral nasal gland, and the olfactory and respiratory mucosa during carcinogen treatment [18].
• Constitutive MGMT mRNA expression was found in bile duct cells, vascular endothelial cells, and fibrous cells; however, weak or negative expression was detected in hepatocytes and Kupffer cells [19].

Associations of Mgmt with chemical compounds

• The purpose of this study was to investigate the association between the mRNA expression level of the Mgmt gene and mutation of the beta-catenin gene in rat colon tumors induced by azoxymethane (AOM) plus dextran sulfate sodium (DSS) [20].
• Modulation of O6-methylguanine-DNA methyltransferase in rat and hamster liver after treatment with dimethylnitrosamine [21].
• Finally, the addition of cycloheximide, an inhibitor of protein synthesis, prior to but not after irradiation, abolished the increase in MGMT activity [16].
• The liver O6-methylguanine-DNA methyltransferase was reduced by hypophysectomy or thyroidectomy and could be increased by treatment with growth hormone or thyroxine [2].
• The radiation-mediated increase in MGMT was blocked by H7, a protein kinase inhibitor, but not by H89, an inhibitor of protein kinase A. Hydroxyl radicals may play a role in the induction mechanism since dimethyl sulfoxide, a radical scavenger, blocked the radiation-mediated increase in MGMT [16].

Other interactions of Mgmt

• Alterations in the activities of DNA topoisomerase enzymes and O6-methylguanine-DNA-methyltransferase in septic rat liver [22].
• Constitutive expression and inducibility of O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in rat liver cells exhibiting different status of differentiation [23].

Analytical, diagnostic and therapeutic context of Mgmt

• The expression level of Mgmt mRNA was determined by reverse transcription-PCR (RT-PCR) [20].
• However, Northern blot analysis showed a two- to threefold elevation in O6-methylguanine-DNA-methyltransferase messenger RNA levels in beta-cells 12 and 24 h after N-methyl-N-nitrosourea treatment [24].
• On the other hand, after exposure to dimethylnitrosamine, inducible MGMT mRNA was rapidly expressed in hepatocytes, especially in the centrilobular area at earlier time points, confirming our previous studies in which enzymatic activity has been measured in different purified cell populations obtained by differential centrifugation [19].
• The intercellular distribution of O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression has been investigated at the individual cell level in the liver of rats treated with dimethylnitrosamine using in situ hybridization [19].
• The amount of MGMT mRNA was then measured by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR) amplification and Southern hybridization [25].

References