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Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1, a member of the mitochondrial carrier family Manganese-containing superoxide dismutase (SOD2) plays a critical role in guarding against mitochondrial oxidative stress and is essential for survival of many organisms. Despite the recognized importance of SOD2, nothing is known regarding the mechanisms by which this nuclear-encoded protein is converted to an active enzyme in the mitochondrial matrix. To search for factors that participate in the posttranslational activation of SOD2, we screened for yeast genes that when mutated lead to SOD2 inactivation and identified a single ORF, YGR257c. The encoded protein localizes to the mitochondria and represents a member of the yeast mitochondrial carrier family. YGR257c was previously recognized as the homologue to human CGI-69, a widely expressed mitochondrial carrier family of unknown function. Our studies suggest a connection with SOD2, and we have named the yeast gene MTM1 for manganese trafficking factor for mitochondrial SOD2. Inactivation of yeast MTM1 leads to loss of SOD2 activity that is restored only when cells are treated with high supplements of manganese, but not other heavy metals, indicative of manganese deficiency in the SOD2 polypeptide. Surprisingly, the mitochondrial organelle of mtm1 Delta mutants shows no deficiency in manganese levels. Moreover, mtm1 Delta mutations do not impair activity of a cytosolic version of manganese SOD. We propose that Mtm1p functions in the mitochondrial activation of SOD2 by specifically facilitating insertion of the essential manganese cofactor. Publications
Luk E, Carroll M, Baker M, and Culotta VC. 2003. Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1, a member of the mitochondrial carrier family Proc Natl Acad Sci U S A100:10353-7.
Prospective detection of codon 249 mutations in p53 in plasma of hepatocellular carcinoma patients
In a multidisciplinary molecular epidemiology study, underlying risk factors for human liver cancer have been investigated. In the past in work in China, a specific missense mutation in the p53 tumor suppressor gene at codon 249 has been reported in over 50% of hepatocellular carcinoma (HCC) tumors and in paired blood samples from areas of high dietary exposure to aflatoxin B1, including Qidong, P.R.C. Using a combination of pre-digestion with HaeIII, PCR and mass spectrometry, the temporality of this mutation in plasma before and after the clinical diagnosis of HCC was examined. Sixteen liver cancer cases, diagnosed between 1997 and 2001, were selected from a prospective cohort of 1638 high-risk individuals in Qidong on the basis of available annual plasma samples spanning the years before and after diagnosis. The codon 249 mutation was detected plasma samples obtained after diagnosis in 7 of the 15 cases (46.7%) with PCR amplifiable DNA, which is in accord with the prevalence of this mutation in HCC. The persistent detection of this mutation in plasma collected annually following diagnosis was statistically significant (p=0.024, two-tailed) in repetitive samples following diagnosis. Moreover, the mutation was detected in plasma of 4 of 8 cases positive at time of diagnosis at least one year and in one case five years prior to diagnosis. Tracking of the marker in pre-diagnostic samples was borderline statistically significant (p=0.066). None of the eighteen healthy US control plasma samples had any detectable mutations. We have therefore found that pre-diagnosis biomarkers of specific p53 mutations can be measured in plasma and this suggests a paradigm for developing these markers for use in prevention and intervention trials. Publications
Jackson, PE, Kuang, SY, Wang, JB, Strickland, PT, Munoz, A, Kensler, TW, Qian, GS and Groopman, JD. 2003. Prospective detection of codon 249 mutations in p53 in plasma of hepatocellular carcinoma patients Carcinogenesis10:1657-1663.
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