کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2589963 1131719 2011 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote pkcδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote pkcδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model
چکیده انگلیسی

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.


► Proteolytically activated PKCδ mediates pesticide dieldrin induced dopaminergic degeneration.
► Tyrosine phosphorylation (Y311) on PKCδ is a key event preceding the PKCδ proteolytic activation.
► Dieldrin induces Fyn kinase activation and PKCδ Y311 phosphorylation in N27dopaminergic neurons.
► Fyn siRNA attenuates dieldrin induced PKCδ Y311 phosphorylation and dopaminergic cell death.
► Fyn kinase is a pro-apoptotic kinase that regulates PKCδ-mediated induced apoptosis.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: NeuroToxicology - Volume 32, Issue 5, October 2011, Pages 567–577
نویسندگان
, , , , ,