title: Manganese superoxide dismutase-mediated inside-out signaling in HaCaT human keratinocytes and SKH-1 mouse skin.
abstract: OBJECTIVE
  Inside-out signaling occurs when changes in organellar activity lead to alterations in cell signaling that culminate at the cell surface. Mitochondria are vital signaling platforms in cells that participate in radiation-induced inside-out signaling. However, the importance of the reactive oxygen species (ROS)-scavenging ability of mitochondria through manganese superoxide dismutase (MnSOD) is not established. Here, we used MnSOD heterozygous knockout and transgenic SKH-1 hairless, albino mice and MnSOD knockdown and overexpressing HaCaT human keratinocytes to study the effects of MnSOD on ultraviolet (UV) radiation-induced inside-out signaling.
  
  
  RESULTS
  There is an inverse correlation between MnSOD expression and UV-induced activation of epidermal growth factor receptor (EGFR), as determined by phosphorylation at Tyr1068, both in vitro and in vivo, which correlates with increased ROS production (as measured by dihydroethidium fluorescence). EGFR activation is dependent on Nox4 expression and Src kinase activation, with Src activation upstream of Nox4 in regulation of EGFR activation. Enhanced EGFR activation in MnSOD knockdown cells is abrogated by treatment with the SOD mimetic MnTnBuOE-2-PyP(5+).
  
  
  CONCLUSIONS
  Our data demonstrate that the ROS-scavenging ability of mitochondria, through the expression of MnSOD, is important for UV-induced inside-out signaling. Decreased MnSOD expression enhances UV-induced activation of different oncogenic signaling pathways through an inside-out signaling-mediated mechanism. Inhibition of inside-out signaling by MnTnBuOE-2-PyP(5+) mimics the effect of endogenous MnSOD, suggesting that pharmacological intervention by SOD mimetics could play an important role in the prevention of aberrant cell signaling, which may contribute to carcinogenesis and may prove valuable for the treatment or prevention of cancer in the future.
authors.affiliation: 1 Graduate Center for Toxicology, University of Kentucky , Lexington, Kentucky.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Holley
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Bakthavatchalu
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D019061:src-Family Kinases / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D019061:src-Family Kinases; D000099156:Superoxide Dismutase 2; C498910:NOX4 protein, human