Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model.
Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model.
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DOI：
10.1016/j.neuro.2011.06.009
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发表时间：
2011-10
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy A
中科院分区：
文献类型：
--
作者：
Saminathan H;Asaithambi A;Anantharam V;Kanthasamy AG;Kanthasamy A
氧化应激和细胞凋亡是帕金森病（PD）多巴胺能变性的两个重要病理生理机制。最近，我们发现蛋白激酶C δ（PKCδ）蛋白水解激活参与了氧化应激诱导的多巴胺能神经元变性，而PKCδ蛋白水解激活之前，PKCδ蛋白酪氨酸残基311（tyr 311）的磷酸化是氧化损伤过程中PKCδ蛋白水解激活的关键事件。在此，我们报告，非受体酪氨酸激酶Fyn显着表达在多巴胺能神经元N27细胞模型。将N27细胞暴露于多巴胺能毒物狄氏剂（60 μM）可迅速激活Fyn激酶、PKCδ-tyr 311磷酸化和蛋白水解裂解。Fyn激酶激活先于caspase-3介导的PKCδ蛋白水解激活。与p60-酪氨酸特异性激酶抑制剂（TSKI）共处理几乎完全减弱了狄氏醇诱导的PKCδ-tyr 311磷酸化及其蛋白水解激活。此外，TSKI几乎完全阻断狄氏醇诱导的凋亡性细胞死亡。为了进一步证实Fyn在PKCδ促凋亡功能中的作用，我们采用了RNAi方法。siRNA介导的Fyn激酶敲低也有效地减弱了狄氏醇诱导的PKCδ-tyr 311磷酸化、caspase-3介导的PKCδ蛋白水解切割和DNA片段化，表明Fyn激酶调节PKCδ的促凋亡功能。总的来说，这些结果首次证明，Fyn激酶是一种促凋亡激酶，在农药暴露的神经毒性模型中调节PKCδ介导的凋亡细胞死亡途径的上游信号。
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. Co-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.
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影响因子：
3.6
作者：
Kanthasamy AG;Kitazawa M;Yang Y;Anantharam V;Kanthasamy A
通讯作者：
Kanthasamy A
影响因子：
3.4
作者：
Kanthasamy, AG;Kitazawa, M;Anantharam, V
通讯作者：
Anantharam, V
影响因子：
4.4
作者：
Elbaz, Alexis;Tranchant, Christine
通讯作者：
Tranchant, Christine
影响因子：
4.8
作者：
Kajimoto, T;Shirai, Y;Saito, N
通讯作者：
Saito, N
农药接触和帕金森病风险：基于家庭的病例对照研究。
影响因子：
2.6
作者：
Hancock, Dana B.;Martin, Eden R.;Mayhew, Gregory M.;Stajich, Jeffrey M.;Jewett, Rita;Stacy, Mark A.;Scott, Burton L.;Vance, Jeffery M.;Scott, William K.
通讯作者：
Scott, William K.