Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human c-rel gene (REL), encoding an NF-kappaB transcription factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro. We have previously shown that certain deletions of C-terminal transactivation sequences enhance REL's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on REL's transforming ability. Mutation of either of two TNFalpha-inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made REL more efficient at transforming chicken spleen cells in vitro. In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired REL's transforming ability, even though it increased REL's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect REL's transforming ability. Transactivation by GAL4-REL fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-REL. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type REL in their ability to transactivate certain kappaB-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming REL mutant REL-S471N in transient assays, but REL-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type REL-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance REL's transforming ability in vitro and suggest that these mutations increase REL-mediated transformation by altering REL's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in REL-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the REL transactivation domain contribute to the development of certain human B-cell lymphomas.
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PMID:Mutations of tumor necrosis factor alpha-responsive serine residues within the C-terminal transactivation domain of human transcription factor REL enhance its in vitro transforming ability. 1602 30

Polymorphisms in genes encoding enzymes involved in estrogen metabolism are held to be candidates for associations with breast disease, since there is evidence that circulating estrogens are associated with breast cancer risk. In this study, we evaluated the frequency of different polymorphisms related with estrogen metabolism [COMT Val158Met, CYP17 (5'UTR, T27C); HSD17beta1 Gly313Ser and MnSOD Val16Ala] in a breast cancer resistant population, the Xavante Indians, and the frequencies were compared with the ones reported in other populations where breast cancer case-control studies dealing with these polymorphisms have been carried out. The data obtained showed that, apart from the MnSOD Val16Ala polymorphism where the frequency of the variant allele was much higher than that reported in other populations, all the others were within the range reported in other populations. Considering these data we carried out a case-control study in the Portuguese population (241 cases and 457 controls) in order to evaluate the potential role of this polymorphism in breast cancer susceptibility. The results obtained did not reveal a significant association between individual genotypes and breast cancer risk. However, when the population was stratified for breast feeding, it was observed that for the patients that never breast fed the presence of the variant allele (Ala) was marginally associated with a decreased risk for this pathology (adjusted OR: 0.575 (0.327-1.011). These data seem to suggest that individuals who never breast fed with MnSOD Val16Ala variant allele are at a lower risk for breast cancer, but larger studies are required to confirm these results.
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PMID:Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17beta1, COMT and MnSOD): possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed. 1696 94

Individual response to oxidative stress, due to exposure to asbestos fibres plays a significant role in the malignant pleural mesothelioma (MPM) etiology. The differential impact on MPM risk of polymorphic alleles of glutathione-S-transferases (GSTs) and manganese superoxide dismutase (MnSOD/SOD2) genes involved in the defence against oxidative damage has been investigated. Ninety cases of MPM and 395 controls were genotyped using the arrayed-primer extension technique. Logistic regression analysis was applied to assess the predictive role of single nucleotide polymorphisms (SNPs) potentially involved in MPM carcinogenesis after adjustment for potential confounders. An increased risk of MPM was found in subjects bearing a GSTM1 null allele (OR = 1.69, 95% CI = 1.04-2.74; p = 0.034), and in those with the Ala/Ala genotypes at codon 16 within MnSOD (OR = 3.07, 95% CI = 1.55-6.05; p = 0.001). A stronger effect of MnSOD was observed among patients without a clear exposure to asbestos fibres. No effect was found for GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes. These findings, if replicated, contribute substantial evidence to the hypothesis that oxidative stress and cellular antireactive oxygen species systems are involved in the pathogenesis and in the natural history of MPM.
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PMID:Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma. 1729 Mar 92

Oxidative stress, associated with aging and inflammation, is likely to play a role in the etiology of prostate cancer. We evaluated potential associations between gene variants that result in reduced neutralization of reactive oxygen species (ROS; MnSOD Ala-16Val, CAT -262 C>T, and GPX1 Pro200Leu) and prostate cancer risk among 724 men with incident prostate cancer who participated in the Carotene and Retinol Efficacy Trial (CARET) cohort, a randomized trial for the prevention of lung cancer among men with a history of smoking and/or asbestos exposure. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression. Nested case-control analyses included study participants with available DNA (n = 533 cases and 1,470 controls), matched for race, age, and length of follow-time. Overall, there were no associations between genotypes of MnSOD, CAT, and GPX1 and prostate cancer risk, although among men diagnosed before age 65, CAT TT genotype was associated with increased risk (OR, 2.0; 95% CI, 0.97-3.95). Further analyses stratified by factors related to environmental oxidative stress exposures did not modify associations. When calculating the number of risk alleles of MnSOD, CAT, and GPX1 hypothetically related to reduced protection against ROS, there was a nonsignificant relationship between prostate cancer and carriage of five or more risk alleles, in comparison to men with less than five risk alleles (OR, 2.0; 95% CI, 0.90-4.42). In conclusion, it does not seem that variants in MnSOD, CAT, or GPX1 have an influence on prostate cancer risk in this cohort of men who were smokers or exposed to asbestos, although it is possible that cumulative defects in protection from oxidative stress may result in increased risk of the disease.
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PMID:Polymorphisms in oxidative stress-related genes are not associated with prostate cancer risk in heavy smokers. 1754 72

Polymorphism in manganese superoxide dismutase gene (Mn-SOD) is a new approach to identify its probable association with urolithiasis. Oxidative stress may be involved in the development of stone formation in the renal system. MnSOD is one of the primary enzymes that directly scavenges potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in urolithiasis risk. This study was conducted to investigate the association of MnSOD gene polymorphism with the risk of urolithiasis. We investigated the MnSOD in 66 stone-forming adults and 72 healthy volunteers. DNA was isolated from peripheral blood and genotyping was performed with PCR-based methods. Then PCR products were cut by BsaW1. Products were run on 3% agarose gel, 246 bp regions were 1-Ala-9, 164 and 82 bp products were determined as 2 Val-9. Chi-square test was used for comparison between patients and controls. In the control group the homozygote Ala allele was significantly higher than in the patient group (P < 0.01). The distribution of Ala/Val and homozygote Val alleles in the patient group was significantly higher than in the control group (P < 0.05). MnSOD genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. This experiment also provides data about antioxidant status and stone formation.
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PMID:Manganese superoxide dismutase (Mn-SOD) gene polymorphisms in urolithiasis. 1762 94

Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; P(trend) = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; P(interaction) = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (</=222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E.
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PMID:Functional variant of manganese superoxide dismutase (SOD2 V16A) polymorphism is associated with prostate cancer risk in the prostate, lung, colorectal, and ovarian cancer study. 1764 72

The aim of the study was to investigate relationship between activity of superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor alpha (TNFalpha) and between Ala-9Val polymorphism in the gene encoding MnSOD (SOD2) and the initial stage and prognosis of the head and neck squamous cell carcinoma (HNSCC). Prospective study cohort comprised 88 patients who underwent surgical treatment for the diagnosis of HNSCC (53 patients were diagnosed with locoregional metastatic spread (N+) at the time of diagnosis). After the initial surgery subjects were followed for the subsequent period of 26 months during which 14 manifested relapse. Genotypes were detected by the PCR-based methodology. Activity of p-SOD, ery-SOD and TNFalpha were determined by ELISA, and the concentration of MDA by high performance liquid chromatography. Genotype and allele frequencies of the Ala-9Val differed neither between groups defined according to the stage of primary disease (TNM), nor between relapse vs. remission groups after the follow-up (p>0.05). Activity of p-SOD was significantly higher in T3/4 stage compared to T1/2 (p=0.01) and was also higher in N+ compared to N0 patients (p=0.002). Carriers of the Ala/Ala genotype had higher p-SOD activity (p=0.04). There was no significant difference in DFI between SOD2 genotype groups (p>0.05), however, the Ala/Ala group exhibited the shortest median DFI. In conclusion, our results suggest that increased p-SOD at the time of the initial treatment for HNSCC is connected with greater extent and nodal metastatic spread of the initial disease and with an earlier relapse of the disease. Progression of the disease might be further modified by the presence of Ala/Ala genotype of the SOD2. Activity of p-SOD could thus offer diagnostic as well as prognostic value.
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PMID:Increased activity of superoxide dismutase in advanced stages of head and neck squamous cell carcinoma with locoregional metastases. 1782 22

Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMT(val158met), using Val-Val homozygotes as reference category, a protective effect for Val-Met heterozygotes (OR=0.63, 95% CI: 0.46-0.86, P=0.004) and Met carriers (OR=0.66, 95% CI: 0.49-0.88, P=0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR=1.30, 95% CI: 1.03-1.65, P=0.026), and A2-A2 homozygotes using A1-A1 as reference category (OR=1.80, 95% CI: 1.03-3.15, P=0.037); (3) in MnSOD Ala-9Val, using Ala-Ala homozygotes as reference category, a protective effect for Ala-Val (OR=0.37, 95% CI: 0.17-0.79, P=0.009) and for Val carriers (OR=0.49, 95% CI: 0.24-1.00, P=0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge. Molecular Psychiatry (2008) 13, 544-556; doi:10.1038/sj.mp.4002142; published online 8 January 2008.
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PMID:Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions. 1818 Jul 54

This study investigated whether there was an interaction between the NQO1 Pro187Ser and MnSOD Ala-9Val gene polymorphisms in the development of tardive dyskinesia (TD). The combined genotypes of T/T in NQO1 Pro187Ser and Val/Val in MnSOD Ala-9Val polymorphisms were found to be independently associated with a significantly higher risk of TD. However, further adequately powered studies will be needed to confirm these preliminary findings.
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PMID:Additive effect between quinine oxidoreductase gene (NQO1: Pro187Ser) and manganese superoxide dismutase gene (MnSOD: Ala-9Val) polymorphisms on tardive dyskinesia in patients with schizophrenia. 1897 34

Reactive oxygen species have been related to the aetiology of cancer as they are known to be mitogenic and therefore capable of tumour promotion. The aim of this study was to assess the role of common variation in three polymorphic genes (MnSOD Ala-9Val, GPX1 Pro198Leu and CAT -262 C > T) coding for antioxidant defence enzymes in modulating individual susceptibility to hepatocellular carcinoma (HCC) using a case-control study (cases = 96 and controls = 222). PCR-RFLP and sequencing methods were used to determine the genotype. Overall, there were no associations between genotypes GPX1 and HCC risk (OR, 1.16; 95% CI, 0.56-2.42; p = 0.685). The MnSOD Ala/Ala and CAT TT genotypes were more frequent in HCC than in control (p = 0.001 and p = 0.072, respectively). Further analyses stratified by gender or HCV infection revealed that men and HCV-infected patients carrying CAT TT genotype had a higher risk to develop HCC when compared with controls (OR = 15.94; 95% CI, 3.48-72.92; p < 0.000001 and 12.01; 95% CI, 0.64-223.63, p = 0.056, respectively). Combined MnSOD Ala/Ala and GPx1 Leu/Leu had a synergistic effect on HCC risk, with an OR of 3.84 (p = 0.029). Furthermore an even more pronounced risk was observed when we combined MnSOD Ala/Ala and CAT TT (OR = 13.60, p = 0.023). It appears that variants in MnSOD, CAT or GPX1 have an influence on HCC risk in this cohort. Furthermore, it is possible that cumulative defects in protection from oxidative stress may result in increased risk of liver cancer in the Moroccan population.
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PMID:Polymorphisms in antioxidant defence genes and susceptibility to hepatocellular carcinoma in a Moroccan population. 1992 44


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