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

Interdisciplinary Program in Molecular and Cellular Biology and Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
Free Radical Biology and Medicine (Impact Factor: 5.71). 05/2008; 44(8):1677-86. DOI: 10.1016/j.freeradbiomed.2008.01.022
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ABSTRACT 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 (Lck-MnSOD) as well as MnSOD+/- mice. The effects of MnSOD on apoptosis, cell cycle, chromosomal instability (CIN), and lymphoma development were 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 premalignant 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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Available from: Brian J Smith, Jun 20, 2014
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    • "It influences the activity of some transcription factors, such as activator protein 1 (AP-1), nuclear factor-kappa B (NFí µí¼…B), and p53 [80] [81]. MnSOD also protects the normal tissues from chromosomal instability, due to various injuries, causing cancer [82]. Moreover, this enzyme modulates the ROS concentration in cancer cells [83] [84]. "
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    01/2014; 2014:476789. DOI:10.1155/2014/476789
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    • "Decreased MnSOD expression levels, gene silencing, inactivating mutations or gene polymorphisms, all have been associated with tumorigenesis , also in the case of lymphoma and leukemia development [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]. Moreover, several reports addressed the importance of MnSOD for T cell differentiation and function [23] [32] [34] [35]. In that respect, our results shed a new light on the understanding of a T cell-specific function of MnSOD, one of the catalytically fastest and thus most intriguing enzymes of the human cell. "
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