title: Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model.
abstract: Oxidative stress and apoptosis are two key pathophysiological mechanisms underlying dopaminergic degeneration in Parkinson's disease (PD). Recently, we identified that proteolytic activation of protein kinase C-delta (PKCδ), a member of the novel PKC family, contributes to oxidative stress-induced dopaminergic degeneration and that phosphorylation of tyrosine residue 311 (tyr311) on PKCδ is a key event preceding the PKCδ proteolytic activation during oxidative damage. Herein, we report that a non-receptor tyrosine kinase Fyn is significantly expressed in a dopaminergic neuronal N27 cell model. Exposure of N27 cells to the dopaminergic toxicant dieldrin (60 μM) rapidly activated Fyn kinase, PKCδ-tyr311 phosphorylation and proteolytic cleavage. Fyn kinase activation precedes the caspase-3-mediated proteolytic activation of PKCδ. Pre-treatment with p60-tyrosine-specific kinase inhibitor (TSKI) almost completely attenuated dieldrin-induced phosphorylation of PKCδ-tyr311 and its proteolytic activation. Additionally, TSKI almost completely blocked dieldrin-induced apoptotic cell death. To further confirm Fyn's role in the pro-apoptotic function of PKCδ, we adopted the RNAi approach. siRNA-mediated knockdown of Fyn kinase also effectively attenuated dieldrin-induced phosphorylation of PKCδ-tyr311, caspase-3-mediated PKCδ proteolytic cleavage, and DNA fragmentation, suggesting that Fyn kinase regulates the pro-apoptotic function of PKCδ. Collectively, these results demonstrate for the first time that Fyn kinase is a pro-apoptotic kinase that regulates upstream signaling of the PKCδ-mediated apoptotic cell death pathway in neurotoxicity models of pesticide exposure.
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011, USA.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Saminathan
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Asaithambi
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004026:Dieldrin / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015386:Hazardous Substances / Q000633:toxicity; D010575:Pesticides / Q000633:toxicity; D051745:Protein Kinase C-delta / Q000502:physiology*; D051381:Rats; D053634:TYK2 Kinase / Q000378:metabolism*
chemical_list: D015386:Hazardous Substances; D010575:Pesticides; D053634:TYK2 Kinase; D051745:Protein Kinase C-delta; D004026:Dieldrin; D004298:Dopamine