Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which plays an important role in chemotherapy, mutagenesis, and carcinogenesis. The specific activity of MGMT in female rat liver can be induced by approximately 20-fold by treatment of the rats with gamma-irradiation. Maximum response occurred 48 h after 15 Gy irradiation. MGMT levels in male rats were induced by only 3-fold. MGMT activity was also induced by irradiation of rat hepatoma H4IIE cells with a 3-fold increase noted after treatment with 3 Gy. Northern analysis and nuclear run-on assays indicated that the induction of MGMT was regulated at the transcriptional level. 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. MGMT activity was also increased by treatment of the cells with H2O2, in accordance with the involvement of activated oxygen species in the induction of MGMT. Finally, the addition of cycloheximide, an inhibitor of protein synthesis, prior to but not after irradiation, abolished the increase in MGMT activity.
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PMID:Irradiation-induced expression of O6-methylguanine-DNA methyltransferase in mammalian cells. 137 30

O6-Methylguanine-DNA methyltransferase (MGMT) is responsible for removal of O6-alkylguanine from DNA induced by alkylating mutagens/carcinogens. To analyze the involvement of O6-alkylguanine in the generation and MGMT in avoidance of various genotoxic effects of alkylating agents, we transfected Chinese hamster ovary (CHO) cells that lack MGMT activity with human MGMT cDNA cloned into a mammalian expression vector (pSV2MGMT). A high proportion (60-80%) of transfectants selected for a cotransfected neo gene survived treatment with high doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-hydroxyethyl-N-chloroethylnitrosourea (HeCNU). Parallel transfections with an expression vector containing the bacterial ada gene (pSV2ada) showed the human MGMT to be more effective than the ada expression vector in mediating alkylation resistance. Various clonal CHO cell lines have been established stably transfected with the human MGMT cDNA. The transfectants expressed human MGMT at levels ranging from 8600 to 210,000 molecules per cell. The high MGMT expressors became strongly resistant to the killing effects of MNNG, HeCNU, N-methyl-N-nitrosourea (MNU) and, to a significant lesser degree, methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS). No killing resistance was observed to N-ethyl-N-nitrosourea (ENU), though the MGMT and ada transfectants showed reduction in mutation frequency induced by this agent. Protection from mutation induction by MGMT (and ada) expression was also demonstrated for MNNG. The transfectants were also protected from the sister chromatid exchange (SCE) inducing and, to a lesser degree, clastogenic effect of MNNG and MNU, and slightly to EMS and MMS. Again no protection was observed towards ENU. Correlations between MGMT activity and resistance to a given end point suggest that, for MNNG, O6-methylguanine is the preponderant toxic, mutagenic and SCE inducing lesion. About 90% of MNNG (and MNU) induced SCEs and nearly all of the MNNG-induced gene mutations seem to be due to this adduct. For alkylation-induced chromosomal aberrations, however, and for cell killing and SCEs induced by MMS, EMS and ENU, other lesions than O6-alkylguanine appear to be of major importance. The data strongly support the view that O6-methylguanine is a genotoxic lesion and MGMT a function decisively involved in avoidance of genotoxic effects in cells exposed to MNNG and related compounds. They indicate also that it is important to take into account the property and mode of action of any given alkylating agent in assessing the protective role of MGMT against alkylation-induced genotoxicity.
Carcinogenesis 1991 Oct
PMID:Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. 165 27

A subclone of a human glioma tumor cell strain which was deficient at O-6-alkylguanine repair was transfected with DNA from an O-6-alkylguanine DNA alkyltransferase-positive human colon tumor cell line (HT29). The transfected subclone, which was selected by its resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), acquired increased resistance to chloroethylnitrosourea (CNU), contained O-6-methylguanine-DNA methyltransferase activity, and failed to accumulate interstrand crosslinks in its DNA upon treatment with CNU. The subclone morphologically resembled its CNU-sensitive parental glioma cell strain. The close correlation between the increased cellular resistance, increased O-6-alkylguanine repair activity and the absence of crosslinking suggests that the formation of DNA crosslinks is one important mechanism of cytotoxicity produced by CNU, and that repair of DNA lesions by O-6-alkylguanine DNA alkyltransferase may partially prevent CNU-induced cytotoxicity.
Carcinogenesis 1986 Sep
PMID:Transfection of DNA from a chloroethylnitrosourea-resistant tumor cell line (MER+) to a sensitive tumor cell line (MER-) results in a tumor cell line resistant to MNNG and CNU that has increased O-6-methylguanine-DNA methyltransferase levels and reduced levels of DNA interstrand crosslinking. 374 31

O6-Methylguanine-DNA methyltransferase (MGMT) plays an important role in protecting cells from the mutagenic potency of alkylating agents. This study addresses the role of DNA methylation in the expression of the human MGMT gene. Southern blot analysis of DNA from human Mer+ (MGMT proficient) and Mer- (MGMT deficient) cell lines demonstrated that the methylation state of a unique SmaI site in the MGMT gene promoter, previously shown by others to be invariably unmethylated in Mer+ cells and methylated in Mer- cells, did not correlate with the Mer phenotype. Neither was there any significant difference in the density of CpG methylation in the MGMT gene 5'-flanking sequences between Mer+ and Mer- cells. On the other hand, the body of the MGMT gene was less methylated in most Mer- cells relative to Mer+ cells, and in three of six Mer- cell lines the gene was essentially methylation-free. Interestingly, the Mer- cells that were hypomethylated in the MGMT gene also tended to be less methylated at other loci. Widespread hypomethylation is a frequent trait in carcinogenesis, and may be involved in development of the frequently found Mer- phenotype.
Carcinogenesis 1995 Aug
PMID:The methylation status of the gene for O6-methylguanine-DNA methyltransferase in human Mer+ and Mer- cells. 763 15

O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that plays an important role in chemotherapy, mutagenesis, and carcinogenesis. Recombinant human MGMT was isolated from an Escherichia coli high performance expression system and purified to homogeneity. The kinetic and DNA-binding properties of the recombinant human MGMT were studied. The purified human MGMT reacted stoichiometrically with methylated DNA under second-order rate kinetics. The rate constant with normal methylated DNA was 1 x 10(9) M-1 min-1 at 37 degrees C. The binding to DNA was the rate determining step in the repair process. Approximately eight base pairs of the DNA substrate were covered by the human MGMT protein. The affinity constant for interaction of DNA to MGMT was approximately 4.7 x 10(5) M-1. The binding to methylated DNA was also examined; the binding affinity to methylated DNA was two times higher than that to unmodified DNA. The interaction with DNA induced a conformational change in the human MGMT protein as monitored by circular dichroism and fluorescence analysis. A similar conformational change was induced by both methylated and unmodified DNA.
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PMID:Kinetic and DNA-binding properties of recombinant human O6-methylguanine-DNA methyltransferase. 842 52

06-Methylguanine-DNA methyltransferase (MGMT) is present in various organisms, from bacteria to human cells, and plays an important role in preventing mutations caused by alkylating substances. To understand better the regulatory mechanism involved in the expression of the gene and to construct a mouse model to investigate roles of the enzyme in carcinogenesis, the genomic sequence for mouse methyltransferase was isolated and characterized. The gene consists of 5 exons and spans over 180 kb, whereas mRNA for the enzyme was less than 1 kb. The promoter region for the gene is GC-rich, contains many Sp1 recognition sequences and lacks typical TATA and CCAAT boxes. Primer extension and S1 mapping revealed the existence of multiple transcription initiation sites, among which a major site was defined as +1. The putative promoter region was placed upstream of the chloramphenicol acetyltransferase (CAT) reporter gene and the construct was introduced into mouse NIH-3T3 cells. Deletion analyses revealed that a sequence from -262 to + 56 carries the basic promoter activity. In addition, an adjacent region, spanning from +56 to +95, carries an E2F-like element that greatly stimulates the frequency of transcription. Alteration of TTTTGGGGC to TTAACGGGC considerably reduced the activity.
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PMID:Organization and expression of the mouse gene for DNA repair methyltransferase. 889 58

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from the O(6) position of guanine in DNA. Repair of O(6)-alkylguanine adducts by tumour cells has been implicated in drug resistance since it reduces the cytotoxicity of alkylating chemotherapeutic agents. We assessed promoter methylation of the MGMT gene in astrocytic brain tumours by methylation-specific PCR. MGMT promoter methylation was detected in 26 of 54 (48%) low-grade diffuse astrocytomas (WHO grade II) and in 12 of 16 (75%) of secondary glioblastomas (WHO grade IV) that had progressed from low-grade astrocytomas. The frequency of MGMT methylation was significantly lower in primary (de novo) glioblastomas (13 of 36, 36%, P = 0.0155). The majority of low-grade astrocytomas with MGMT methylation (24/26, 92%) contained a TP53 mutation, whereas only 11 out of 28 (39%) cases without MGMT methylation carried a TP53 mutation (P < 0.0001). Furthermore, G:C --> A:T transition mutations at CpG sites were significantly more frequent in low-grade astrocytomas with MGMT methylation (15/26, 58%) than in those without (3/28, 11%, P = 0.0004). These results suggest that loss of MGMT expression as a result of promoter methylation, which frequently occurs at an early stage in the pathway leading to secondary glioblastomas, appears to be associated with increased frequency of TP53 mutations, in particular G:C --> A:T transitions.
Carcinogenesis 2001 Oct
PMID:Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C --> A:T mutations of the TP53 tumor suppressor gene. 1157 14

Methylating agents are involved in bladder carcinogenesis. O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes methyl group from O6-methylguanine and thus plays an important role in the etiology of cancer. We hypothesized that two MGMT polymorphisms in exon 3, C16195T (or MGMT L53L) and C16286T (or MGMT L84F) are associated with risk of bladder cancer. In a hospital-based case-control study of 167 patients with bladder cancer and 204 cancer-free controls frequency-matched by age, sex, smoking status, and alcohol use, we genotyped these two MGMT polymorphisms. We found that these two polymorphisms alone had a non-significant main effect on risk of bladder cancer. However, when these two polymorphisms were evaluated together, individuals with the combined genotypes or haplotypes with one or more variant alleles (i.e. the 16195T and 16286T alleles) had statistically significantly increased risk of bladder cancer (adjusted odd ratio [OR]=1.67, 95% confidence interval [CI], 1.01-2.77) compared with those with no variant allele. In the stratification analysis, the risk of bladder cancer was increased in a dose-response manner as the age increased (P(trend)=0.010), and the increased risk was more pronounced among old subjects (>65 years) (adjusted OR=2.51, 95% CI, 1.05-6.04), men (1.76, 1.00-3.10), and non-drinkers (1.91, 1.08-3.36). In conclusion, these two MGMT polymorphisms may jointly play a role, in the etiology of bladder cancer in southern Chinese population. Larger studies are warranted to validate our findings.
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PMID:Exon 3 polymorphisms and haplotypes of O6-methylguanine-DNA methyltransferase and risk of bladder cancer in southern China: a case-control analysis. 1588 89

Around 200-600 million Asians chew areca (also called betel), which contains a mixture of areca nut and other ingredients. Epidemiological evidences indicated that areca use is tightly linked to oral carcinogenesis. This study investigated the effects of ripe areca nut extract (ANE) on cultured normal human oral keratinocyte (NHOK). Acute subtoxic ANE treatment inhibited DNA synthesis and induced cell cycle arrest at G1 phase in early passage (< 4th passage) cells. This was accompanied by a slight increase in the sub-G1 cellular fraction. O6-Methylguanine-DNA methyltransferase (MGMT), Hsp27 and p38MAPK was upregulated. p16 and p21 were remarkably upregulated early and declined afterwards. In contrast, the increase of dephosphorylated Rb seemed to be secondary to the episodes of p16 and p21 upregulation. To simulate the chronic areca exposure in vivo, constant ANE treatment in serial NHOK culture was performed. It resulted in a significant decrease in the population doubling, increase in senescence-associated beta-galactosidase (SA-beta-Gal) and decrease in cell proliferation in NHOK of late passages (> or = 4th passage). Induction of senescence-associated phenotypes, G2/M accumulation and genomic instability following long-term ANE treatment were also observed in a low-grade oral carcinoma cell. ANE-treated NHOK also had a higher nuclear factor-kappaB (NF-kappaB) fraction and a lower cytosolic IkappaBalpha level relative to the control in late passages. Moreover, electrophoretic mobility shift assay (EMSA) indicated that ANE treatment shifted the NF-kappaB complex from high mobility position to lower mobility position in late-passaged NHOK. ANE treatment also upregulated IL-6 and cyclooxygenase-2 (COX-2) mRNA expressions in late-passaged NHOK. In summary, our findings suggest that ANE induces the cell cycle arrest at G1/S phase and the occurrence of senescence-associated phenotypes of NHOK. The upregulation of p38MAPK, p16, p21, NF-kappaB, IL-6 and COX-2 are likely to participate in the control of these impacts.
Carcinogenesis 2006 Jun
PMID:Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. 1647 77

Morphologically, early colorectal tumors are divided into two groups, protruded-type tumors and flat-type tumors. Although some studies have shown genetic alterations in protruded-type tumors, little is known about genetic and epigenetic alterations in flat-type tumors, as well as pT1 (early invasive) colorectal cancers (CRCs). In the current study, we compared the frequencies of genetic and epigenetic alterations of the RAS-RAF and Wnt signaling pathways in flat-type and protruded-type tumors. In addition, we investigated the relationship between those alterations and invasive potential of pT1 CRCs. Methylations of RASSF2, O-6-methylguanine-DNA methyltransferase (MGMT), Wnt inhibitory factor-1 (WIF-1), EPHB2, CDKN2A and MLH1 were detected in 44.3, 30.3, 81.4, 7.5, 43.6 and 13.4% of the 307 early colorectal tumors, respectively. Mutations of KRAS, BRAF, catalytic subunit alpha of phosphatidylinositol 3'-kinase (PIK3CA) and beta-catenin were detected in 25.4, 4.6, 1.6 and 9.4% of those tumors, respectively. Methylations of MGMT, WIF-1 and CDKN2A were detected in significantly higher percentages of protruded-type tumors than in flat-type tumors. Mutation of at least one gene was detected in a significantly higher percentage of flat-type tumors than in protruded-type tumors. RASSF2 methylation was correlated significantly with KRAS, BRAF or PIK3CA mutation. Multiple logistic analysis showed that lymphatic invasion and RASSF2 methylation with KRAS, BRAF or PIK3CA mutation were independent risk factors for venous invasion in pT1 CRCs. In conclusion, since genetic alterations of these pathways have frequently occurred in flat-type tumors, flat-type tumors seem to have a distinct genetic profile different from that of protruded-type tumors. RASSF2 methylation with oncogenic activation is a promising biomarker for predicting invasive potential of pT1 CRCs.
Carcinogenesis 2007 Jun
PMID:Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. 1718 69


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