Suppression of p53-activated gene, PAG608, attenuates methamphetamine-induced neurotoxicity
Suppression of p53-activated gene, PAG608, attenuates methamphetamine-induced neurotoxicity
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DOI：
10.1016/j.neulet.2006.12.036
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发表时间：
2007-03-13
影响因子：
2.5
通讯作者：
Ogawa, Norio
中科院分区：
文献类型：
--
作者：
Asanuma, Masato;Miyazaki, Ikuko;Ogawa, Norio
p53 激活基因 608 (PAG608) 是一种促凋亡基因，在氧化应激诱导的神经元细胞凋亡中受 p53 表达激活和调节。在这项研究中，我们确定了 PAG608 在甲基苯丙胺诱导的神经毒性中的作用。用 2 mM 甲基苯丙胺处理小鼠多巴胺能 CATH.a 细胞，3 小时后 PAG608 表达增加，随后磷酸化 p53 表达增加。 PAG608 反义 cDNA 的瞬时转染或使用 PAG608 小干扰 RNA 的 RNA 干扰显着减弱了由于甲基苯丙胺 (1-4 mM) 暴露而引起的 CATH.a 细胞活力的剂量依赖性下降。在含有血清素而不是多巴胺的单胺能神经元 B65 细胞中，甲基苯丙胺诱导的细胞死亡也受到 PAG608 反义 cDNA 瞬时转染的显着但部分保护。此外，与对照 PC12 细胞中细胞活力的显着降低相比，PAG608 反义 cDNA 的稳定表达几乎完全阻止了由甲基苯丙胺 (1-5 mM) 产生的 PC 12 细胞的细胞死亡。我们的结果表明，使用 PAG608 反义 cDNA 或小干扰 RNA 瞬时和稳定转染抑制 PAG608 可减弱甲基苯丙胺诱导的各种单胺能神经元细胞的死亡，表明单胺能细胞中甲基苯丙胺的神经毒性至少部分与 PAG608 表达的诱导有关。 (c) 2006 Elsevier Ireland Ltd. 保留所有权利。
The p53-activated gene 608 (PAG608) is a proapoptotic gene activated and regulated by p53 expression in oxidative stress-induced apoptosis of neuronal cells. In this study, we determined the role of PAG608 in methamphetamine-induced neurotoxicity. Treatment of mouse dopaminergic CATH.a cells with 2 mM methamphetamine increased PAG608 expression at 3 h followed by increase in phosphorylated p53 expression. Transient transfection of PAG608 antisense cDNA or RNA interference using PAG608 small interfering RNA significantly attenuated the dose-dependent decrease in cell viability of CATH.a cells by methamphetamine (1-4 mM) exposure. In monoaminergic neuronal B65 cells, which contain serotonin rather than dopamine, methamphetamine-induced cell death was also significantly but partially protected by transient transfection of PAG608 antisense cDNA. Furthermore, cell death of PC 12 cells produced by methamphetamine (1-5 mM) was almost completely prevented by stable expression of PAG608 antisense cDNA, compared with significant reduction of cell viability in control PC12 cells. Our results showed that suppression of PAG608 using transient and stable transfection with PAG608 anti sense cDNA or small interfering RNA attenuates methamphetamine-induced death of various monoaminergic neuronal cells, suggesting that methamphetamine neurotoxicity in monoaminergic cells is related, at least in part, to induction of PAG608 expression. (c) 2006 Elsevier Ireland Ltd. All rights reserved.