The essential role of ERK in 4-oxo-2-nonenal-mediated cytotoxicity in SH-SY5Y human neuroblastoma cells.
The essential role of ERK in 4-oxo-2-nonenal-mediated cytotoxicity in SH-SY5Y human neuroblastoma cells.
复制标题
DOI：
10.1111/j.1471-4159.2009.05883.x
复制
发表时间：
2009-03
影响因子：
4.7
通讯作者：
Lee HG
中科院分区：
文献类型：
--
作者：
Lee HP;Zhu X;Zhu X;Skidmore SC;Perry G;Sayre LM;Smith MA;Lee HG
以前的研究表明，脂质过氧化副产物，如4-羟基壬烯醛（HNE）和4-氧代-2-壬烯醛（ONE），诱导多种细胞类型的细胞死亡，部分通过调节细胞内信号通路。然而，所涉及的具体机制，特别是ONE，尚不清楚，而c-Jun N-末端激酶（JNK）已被证明是必不可少的HNE介导的细胞毒性。在本研究中，我们研究了丝裂原活化蛋白激酶（MAPK）信号通路在ONE诱导的SH-SY 5 Y人神经母细胞瘤细胞毒性中的作用，发现ONE强烈诱导细胞外信号调节激酶（ERK）和JNK的磷酸化，但对p38 MAPK没有影响。有趣的是，细胞短暂暴露于ONE导致细胞死亡，这与HNE介导的毒性形成对比。重要的是，阻断ERK途径而非JNK途径保护细胞免受ONE诱导的细胞毒性，表明ONE介导的细胞毒性机制与HNE介导的细胞毒性机制之间存在显著差异。此外，ERK的抑制减少了ONE诱导的p53磷酸化（细胞应激反应的关键调节剂）和聚（ADP-核糖）聚合酶（PARP）的蛋白水解裂解（细胞凋亡的标志）。总之，这些数据强烈表明ERK在ONE介导的细胞毒性中起重要作用，并且ERK是p53介导的细胞凋亡的上游组分。
Previous studies suggest that lipid peroxidation byproducts, such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE), induces cell death in a wide variety of cell types, partly by modulating intracellular signaling pathways. However, the specific mechanisms involved, particularly for ONE, are unclear while c-Jun N-terminal kinase (JNK) has been shown to be essential in HNE-mediated cytotoxicity. In this study, we examined the role of mitogen-activated protein kinases (MAPK) signaling pathways in ONE-induced cytotoxicity in SH-SY5Y human neuroblastoma cells and found that ONE strongly induces the phosphorylation of extracellular signal-regulated kinase (ERK) and JNK, but no change in p38 MAPK. Interestingly, a transient exposure of the cells to ONE resulted in cell death, which contrasts with HNE-mediated toxicity. Importantly, blocking the ERK pathway, but not the JNK pathway, protected cells against ONE-induced cytotoxicity indicating a striking difference between the ONE-mediated cytotoxicity mechanism and that of HNE. Furthermore, inhibition of ERK reduced ONE-induced phosphorylation of p53, a key modulator of the cellular stress response, and the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), a hallmark of apoptosis. Overall, these data strongly suggest that ERK plays an essential role for ONE-mediated cytotoxicity and that ERK is an upstream component of p53-mediated apoptosis.
登录
查看更多内容
影响因子：
4.1
作者：
Pollack, Michael;Yang, In-Young;Moriya, Masaaki
通讯作者：
Moriya, Masaaki
影响因子：
56.9
作者：
Lee, SH;Oe, T;Blair, IA
通讯作者：
Blair, IA
DOI：
10.1073/pnas.0502979102
发表时间：
2005-09-13
影响因子：
11.1
作者：
Ridnour, LA;Isenberg, JS;Wink, DA
通讯作者：
Wink, DA
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
19.6
作者：
Arany, I;Megyesi, JK;Safirstein, RL
通讯作者：
Safirstein, RL