Cloning, mapping and RNA analysis of the human methionine synthase gene

Li, Yunan N.; Gulati, Sneha; Baker, Priscilla J.; Brody, Lawrence C.; Banerjee, Ruma; Kruger, Warren D.

doi:10.1093/hmg/5.12.1851

Cited by 134 publications

(67 citation statements)

References 29 publications

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“…To date, studies have shown that the dysfunctional mutations in the MTR gene contribute to an elevation of plasma homocysteine levels as a consequence of altered folate metabolism and that defects in MTR activity may be important in tumorigenesis (33). Under these circumstances, DNA synthesis may be disturbed by a dysfunctional mutation in the MTR and MTRR genes by means of affecting transformation of 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolate, leading to altered DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

Zhang¹,

Shi²,

Liu³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Although tobacco and alcohol use are the major risk factors, folate deficiency has been implicated in the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) in the folate metabolic pathway are associated with SCCHN risk. In a hospital-based case-control study of 721 SCCHN cases and 1,234 controls of non-Hispanic Whites, frequency matched by age, sex, and smoking status, we genotyped the MTR A2756G and MTRR G66A polymorphisms. We found that the MTR variant AG and AG/GG genotypes were associated with a significantly increased SCCHN risk [adjusted odd ratio (OR) 1.31; 95% confidence interval (95% CI), 1.07-1.60 for AG and OR, 1.28; 95% CI, 1.05-1.56 for AG/GG] compared with the AA genotype. In contrast, the MTRR variant AA genotype was associated with a significantly decreased SCCHN risk (OR, 0.68; 95% CI, 0.52-0.90) compared with the 66GG genotype. When the two polymorphisms were evaluated together by the number of risk alleles, the SCCHN risk was significantly increased in a dose-dependent manner (P trend = 0.002). The risk of SCCHN was 1.47 (95% CI, 1.08-1.99) for one risk allele, 1.67 (95% CI, 1.23-2.27) for two risk alleles, and 1.74 (95% CI, 1.18-2.54) for three or four risk alleles compared with the wild-type (0 risk allele) genotype. In conclusion, our data provide evidence that support the association between the MTR A2756G and MTRR G66A polymorphisms and SCCHN risk and that these two polymorphisms may have a joint effect on risk of SCCHN.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

Zhang¹,

Shi²,

Liu³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The two RNA bands that hybridize to the methionine synthase probe have been observed previously (9,ll). The shorter cDNA has been sequenced completely (9). The 10 kb band is apparently a preprocessed form of the 7.5 kb message, since it hybridizes to a probe complementary to intron 5 (11).…”

Section: 5mentioning

confidence: 99%

Posttranscriptional Regulation of Mammalian Methionine Synthase by B12

Gulati

Brody

Banerjee

1999

Biochemical and Biophysical Research Communications

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“…We examined MS protein levels by Western analysis. The antiserum was generated against purified porcine MS, but it cross-reacts with human, mouse, and Escherichia coli MS due to the high degree of evolutionary conservation of the MS protein (21). Among the 14 cell lines, we saw no significant difference in steadystate MS levels, with one exception (Fig.…”

Section: Ms Protein Expression and Mutation Analysismentioning

confidence: 92%

Human Breast Cancer and Alterations in Methylthioadenosine Phosphorylase

Kruger¹

2002

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE June 2001 REPORT TYPE AND DATES COVEREDAnnual (15 May 00 -14 May 01) TITLE AND SUBTITLE Human Breast Cancer and Alterations in Methylthioadenosine Phosphorylase AUTHOR(S)Warren D. Kruger, Ph.D. Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the pathway which converts methylthioadenosine (MTA) into methionine and adenine. The MTAP gene is frequently deleted in a variety of different cancers. Our lab has found a link between loss of MTAP expression and the phenomena of methionine dependent growth, defined as the inability to grow on media containing methionine's metabolic precursor homocysteine. Thus cells lacking MTAP seem to require excess methionine for growth. Other labs have shown that cells lacking MTAP have increased sensitivity to purine biosynthetic inhibitors such as methotrexate and 5,10-dideazatetrahydrofolate. These observations suggest that an effective two pronged strategy could be used to eliminate MTAP negative breast cancer cells in vivo. Over the past year we have created isogenic breast cancer derived cell lines, one that is deleted for MTAP and one that has had it reintroduced. We have discovered that the cell line with MTAP reintroduced can now use MTA to make methionine, but is still unable to grow on media lacking homocysteine. This result suggests that MTAP deletion is not the primary cause of methionine dependent growth. Our MTAP deleted cells have increased sensitivity to growth in low levels of methionine and are more sensitive to drugs that inhibit purine biosynthesis. These results suggest that these treatments may be useful in treating MTAP deficient cancers in vivo. We have also examined primary breast tumor material for MTAP expression and find that at least 20% of human breast tumors are MTAP deficient. Figure 1 for metabolic pathway diagram). The MTAP gene is located adjacent to the pl6 tumor suppressor gene and is frequently found homozygously deleted in a variety of different cancers (1-4). Our lab has found a link between loss of MTAP expression and the phenomena of methionine dependent growth. Methionine dependence refers to the inability of certain tumor derived cell lines to grow on media containing homocysteine, a metabolic precursor to methionine (5). Thus cells lacking MTAP seem to require excess methionine for growth. Other labs ...

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Cloning, mapping and RNA analysis of the human methionine synthase gene

Cited by 134 publications

References 29 publications

Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

Posttranscriptional Regulation of Mammalian Methionine Synthase by B12

Human Breast Cancer and Alterations in Methylthioadenosine Phosphorylase

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