title: Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma.
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.
authors.affiliation: Interdisciplinary Program in Molecular and Cellular Biology and Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: van de Wetering
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Coleman
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D043171:Chromosomal Instability; D004195:Disease Models, Animal; D018628:Gene Dosage; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494827:Bax protein, mouse; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D013482:Superoxide Dismutase