title: In situ reduction of oxidative damage, increased cell turnover, and delay of mitochondrial injury by overexpression of manganese superoxide dismutase in a multistage skin carcinogenesis model.
abstract: To study early subcellular pathologic changes of tumorigenesis in mouse skin and possible modulation by overexpression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD), skin keratinocytes from nontransgenic (Ntg) and transgenic (TgH) mice overexpressing MnSOD topically treated with one dose of 7,12-dimethylbenz(a)anthracene (DMBA) and a subsequent dose of 12-O-tetradecanoylphorbol 13-acetate (TPA) were analyzed in situ for levels of MnSOD and the oxidative damage product 4-hydroxy-2-nonenal (4HNE)-modified proteins using specific antibodies and immunogold electron microscopy. At all selected time points analyzed after TPA treatment, there was more MnSOD immunoreactive protein in mitochondria of keratinocytes of TgH mice than Ntg mice. Compared with untreated groups, there was a large increase in 4HNE-modified proteins at 6-24 h after TPA treatment, and this increase was larger in Ntg than TgH mice. Indices of mitosis and apoptosis of keratinocytes were greater in DMBA/TPA-treated TgH than Ntg mouse skin. Mitochondrial injury detected by transmission electron microscopy was delayed in keratinocytes of TgH compared with Ntg mice. The present study demonstrated that overexpression of MnSOD not only protected cells from oxidative damage, but also affected cell turnover kinetics. Thus, previously identified reduction in papilloma formation observed in TgH mice is correlated with mitochondrial events.
authors.affiliation: Pathology and Laboratory Medicine Service, William S. Middleton Veterans Memorial Hospital, Madison, WI 53705, USA. toberley@facstaff.wisc.edu
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Yi
authors.initials: Y
authors.lastname: Xue
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: Kelley
authors.initials: K
authors.lastname: Kiningham
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
authors.forename: Daret K
authors.initials: DK
authors.lastname: St  Clair
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D015127:9,10-Dimethyl-1,2-benzanthracene; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen