title: Effects of butyltins on mitogen-activated-protein kinase kinase kinase and Ras activity in human natural killer cells.
abstract: Butyltins (BTs) contaminate the environment and are found in human blood. BTs, tributyltin (TBT) and dibutyltin (DBT) diminish the cytotoxic function and levels of key proteins of human natural killer (NK) cells. NK cells are an initial immune defense against tumors, virally infected cells and antibody-coated cells and thus critical to human health. The signaling pathways that regulate NK cell functions include mitogen-activated protein kinases (MAPKs). Studies have shown that exposure to BTs leads to activation of specific MAPKs and MAPK kinases (MAP2Ks) in human NK cells. MAP2K kinases (MAP3Ks) are upstream activators of MAP2Ks, which then activate MAPKs. The current study examined if BT-induced activation of MAP3Ks was responsible for MAP2K and thus, MAPK activation. This study examines the effects of TBT and DBT on the total levels of two MAP3Ks, c-Raf and ASK1, as well as activating and inhibitory phosphorylation sites on these MAP3Ks. In addition, the immediate upstream activator of c-Raf, Ras, was examined for BT-induced alterations. Our results show significant activation of the MAP3K, c-Raf, in human NK cells within 10 min of TBT exposure and the MAP3K, ASK1, after 1 h exposures to TBT. In addition, our results suggest that both TBT and DBT affect the regulation of c-Raf.
authors.affiliation: Department of Biological Sciences, Tennessee State University, Nashville, TN, USA.
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Celada
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Whalen
mesh_terms: D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009947:Organotin Compounds / Q000633:toxicity*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C056189:di-n-butyltin; C011559:tributyltin; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ASK1; MAPK/ERK Pathway; Natural Killer cells; Ras; butyltin; c-Raf (Raf1)
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