Synthesis and processing of the precursor for human mangano-superoxide dismutase

Wispé, Jonathan R.; Clark, Jean C.; Burhans, Michael S.; Kropp, K; Korfhagen, Thomas R.; Whitsett, Jeffrey A.

doi:10.1016/0167-4838(89)90058-7

Cited by 181 publications

(100 citation statements)

References 30 publications

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“…Immunoblot analysis revealed a marked increase in protein expression in the Lck-MnSOD versus the non-transgenic control mice ( Figure 3A and B). Importantly, the precursor protein was not detected in these lysates suggesting the mitochondrial leader sequence was efficiently removed when the protein was imported into the mitochondria [29]. However, we cannot exclude the expression of MnSOD in non-mitochondrial compartments.…”

Section: Generation Of Lck-mnsod Transgenic Micementioning

confidence: 87%

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Wetering

Coleman

Spitz

et al. 2008

Free Radical Biology and Medicine

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Increased reactive oxygen species (ROS) such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady state levels of key antioxidant enzymes with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic mouse models. We examined the impact of MnSOD expression in the development of T cell lymphoma in mice expressing proapoptotic Bax. Lck-Bax38/1 transgenic mice were crossed to mice overexpressing MnSOD (LckMnSOD) as well as MnSOD +/− mice. The effect of MnSOD on apoptosis, cell cycle, chromosomal instability (CIN), and lymphoma development was determined. The apoptotic and cell cycle phenotypes observed in thymocytes from control and Bax transgenic mice were unaffected by variations in MnSOD levels. Remarkably, increased gene dosage of MnSOD significantly decreased aneuploidy in pre-malignant thymocytes as well as the onset of tumor formation in Lck-Bax38/1 mice. The observed effects of MnSOD support a role for ROS in CIN and tumor formation in this mouse model of T cell lymphoma.

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Section: Generation Of Lck-mnsod Transgenic Micementioning

confidence: 87%

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Wetering

Coleman

Spitz

et al. 2008

Free Radical Biology and Medicine

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“…According to these published data, results presented in Figure 2a clearly showed that PMA treatment leads to a signi®cant increase in MnSOD mRNA level in both MCF-7 (compare lanes 1 and 2) and MCF-7/R-A1 cells (compare lanes 5 and 6). This is noticeable for both 1 and 4 kb mRNA species, generated by alternate polyadenylation (Wispe et al, 1989). Interestingly, SOD2 mRNA level is further increased in PMApretreated MCF-7/RA-1 cells, following g-irradiation at a dose of 6 Gy ( Figure 2a (a) MCF-7 and MCF-7/R-A1 cell lines were transfected with the luciferase expression plasmid pE1B-hWAF1 (wt-p53RE) or pE1B-hWAF1-mut (having a mutated p53RE).…”

Section: Resultsmentioning

confidence: 99%

Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

et al. 2001

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p53 regulates the transcription of a number of genes among which are dierent redox-related genes. It has been proposed that these genes can induce a cellular oxidative stress leading to p53-dependent apoptosis (Polyak et al., 1997). MnSOD, the product of superoxide dismutase 2 (SOD2) gene, is one of the major cellular defences against oxidative stress. We demonstrate here that p53 is able to repress SOD2 gene expression and that this repression takes place at promoter level. We show the importance of this regulation for the p53 function, by demonstrating that an overexpression of MnSOD decreases p53-mediated induction of apoptosis. Moreover, we demonstrate that MnSOD overexpression decreases p53-gene expression at the promoter level. These ®ndings raise the hypothesis that p53 and SOD2 genes are mutually regulated leading to the modulation of various cellular processes including apoptosis. Oncogene (2001) 20, 430 ± 439.

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“…16 Characterization of the secondary structure and the stability of the recombinant protein rMnSOD was then investigated. The far-UV CD spectra of rMnSOD indicated that the secondary structure of the protein is similar to that of human MnSOD as shown by its crystallographic structure.…”

Section: Discussionmentioning

confidence: 99%

“…15 The molecular weight of the LSAtype MnSOD is about 30 kDa, as estimated by SDS-PAGE, 10 which is significantly higher than the value of 24 kDa calculated for human native MnSOD. 16 Finally, and more importantly, when injected in vitro or in vivo, the LSA-type MnSOD permeates and selectively kills tumour cells, provided that they express oestrogen receptors and low levels of catalase. In contrast, normal cells are not affected by the protein, making the cytotoxic activity of LSAtype MnSOD specific for tumour cells.…”

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confidence: 99%

Biophysical and biochemical characterization of a liposarcoma‐derived recombinant MnSOD protein acting as an anticancer agent

Mancini¹,

Borrelli²,

Schiattarella³

et al. 2008

Intl Journal of Cancer

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A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or 68 Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with 125 I-and 131 I-labelled proteins confirmed that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism. '

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Synthesis and processing of the precursor for human mangano-superoxide dismutase

Cited by 181 publications

References 30 publications

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

Biophysical and biochemical characterization of a liposarcoma‐derived recombinant MnSOD protein acting as an anticancer agent

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