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1.  Enhanced expression of mitochondrial superoxide dismutase leads to prolonged in vivo cell cycle progression and up-regulation of mitochondrial thioredoxin 
Free radical biology & medicine  2010;48(11):1501-1512.
Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated MnSOD levels have been shown to reduce tumor growth in part by suppressing cell proliferation. Studies with fibroblasts have shown that increased MnSOD expression prolongs cell cycle transition time in G1/S and favors entrance into the quiescent state. To determine if the same effect occurs during tissue regeneration in vivo, we used a transgenic mouse system with liver-specific MnSOD expression and a partial hepatectomy paradigm to induce synchronized in vivo cell proliferation during liver regeneration. We show in this experimental system that a 2.6 fold increase in MnSOD activities leads to delayed entry into S phase, as measured by reduction in bromodeoxyuridine (BrdU) incorporation, and decreased expression of proliferative cell nuclear antigen (PCNA). Thus, compared to control mice with baseline MnSOD levels, transgenic mice with increased MnSOD expression in the liver have 23% fewer BrdU positive cells and a marked attenuation of PCNA expression. The increase in MnSOD activity also leads to an increase of the mitochondrial form of thioredoxin (thioredoxin 2), but not of several other peroxidases examined, suggesting the importance of thioredoxin 2 in maintaining redox balance in mitochondria with elevated levels of MnSOD.
PMCID: PMC2945707  PMID: 20188820
MnSOD; partial hepatectomy; mitochondria; thioredoxin 2; liver regeneration; cell cycle progression
2.  Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice 
Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology.
PMCID: PMC2759571  PMID: 19633237
Oxidative damage; Mn superoxide dismutase; Pathology; Aging
3.  The in vivo Gene Expression Signature of Oxidative Stress 
Physiological genomics  2008;34(1):112-126.
How higher organisms respond to elevated oxidative stress in vivo is poorly understood. Therefore, we measured oxidative stress parameters and gene expression alterations (Affymetrix arrays) in the liver caused by elevated reactive oxygen species induced in vivo by diquat or by genetic ablation of the major antioxidant enzymes, CuZn-Superoxide Dismutase (Sod1) and Glutathione Peroxidase-1 (Gpx1).
Diquat (50 mg/kg) treatment resulted in a significant increase in oxidative damage within 3 to 6 hours in wild type mice without any lethality. In contrast, treating Sod1−/− or Gpx1−/− mice with a similar concentration of diquat resulted in a significant increase in oxidative damage within an hour of treatment and was lethal, i.e., these mice are extremely sensitive to the oxidative stress generated by diquat. The expression response to elevated oxidative stress in vivo does not involve an upregulation of classical antioxidant genes, though long-term oxidative stress in the Sod1−/− mice leads to a significant upregulation of thiol antioxidants (e.g., Mt1, Srxn1, Gclc, Txnrd1), which appears to be mediated by the redox-sensitive transcription factor, Nrf2. The main finding of our study is that the common response to elevated oxidative stress, with diquat treatment in wild type, Gpx1−/−, Sod1−/− mice and in untreated Sod1−/− mice, is an upregulation of p53 target genes (p21, Gdf15, Plk3, Atf3, Trp53inp1, Ddit4, Gadd45a, Btg2, Ndrg1). A retrospective comparison with previous studies shows that induction of these p53-target genes is a conserved expression response to oxidative stress, in vivo and in vitro, in different species and different cells/organs.
PMCID: PMC2532791  PMID: 18445702
Oxidative Stress; Gene Expression; p53-target genes; Sod1; Gpx1
4.  The overexpression of major antioxidant enzymes does not extend the lifespan of mice 
Aging Cell  2008;8(1):73-75.
We evaluated the effect of overexpressing antioxidant enzymes on the lifespans of transgenic mice that overexpress copper zinc superoxide dismutase (CuZnSOD), catalase, or combinations of either CuZnSOD and catalase or CuZnSOD and manganese superoxide dismutase (MnSOD). Our results show that the overexpression of these major antioxidant enzymes, which are known to scavenge superoxide and hydrogen peroxide in the cytosolic and mitochondrial compartments, is insufficient to extend lifespan in mice.
PMCID: PMC2667893  PMID: 19077044
aging; antioxidant enzymes; transgenic and knockout mice
5.  Absence of Mitochondrial Superoxide Dismutase Results in a Murine Hemolytic Anemia Responsive to Therapy with a Catalytic Antioxidant 
Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2−, and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2+/+, Sod2−/−, and Sod2+/− fetal liver recipients. However, animals receiving Sod2−/− cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress–induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.
PMCID: PMC2193409  PMID: 11304553
transplantation (fetal liver); oxidative stress; antioxidant; stem cells; SOD2
7.  Genes contributing to prion pathogenesis 
The Journal of general virology  2008;89(Pt 7):1777-1788.
Prion diseases are caused by conversion of a normally folded, nonpathogenic isoform of the prion protein (PrPC) to a misfolded, pathogenic isoform (PrPSc). Prion inoculation experiments in mice expressing homologous PrPC molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analyzed prion incubation times in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 gene candidates, because their products either colocalize with PrP, are associated with Alzheimer’s disease, are elevated during prion disease, or function in PrP-mediated signaling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrPC, our data show that many genes previously implicated in prion replication have no discernable effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of amyloid beta (A4) precursor protein (App) or interleukin 1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13%, 16%, and 19%, respectively.
PMCID: PMC2828448  PMID: 18559949

Results 1-8 (8)