How protein kinase C activation protects nerve cells from oxidative stress-induced cell death
How protein kinase C activation protects nerve cells from oxidative stress-induced cell death
复制标题
DOI：
10.1523/jneurosci.21-09-02929.2001
复制
发表时间：
2001-05-01
影响因子：
5.3
通讯作者：
Maher, P
中科院分区：
文献类型：
--
作者：
Maher, P
氧化应激与多种神经系统疾病中发生的神经细胞死亡有关，而蛋白激酶 C (PKC) 活性的丧失与损伤的严重程度有关。然而，应激、PKC 和细胞死亡之间的功能关系尚不清楚。我使用对氧化应激特别敏感的永生化海马细胞系，证明佛波酯十四酰佛波醇乙酸酯 (TPA) 激活 PKC，通过刺激复杂的蛋白质磷酸化途径来抑制细胞死亡。 TPA 处理导致细胞外信号调节激酶 (ERK) 和 c-Jun NH2 末端激酶 (JNK) 快速激活、p38 丝裂原激活蛋白激酶 (MAPK) 失活以及 PKC δ 下调。抑制 ERK 或 JNK 激活可阻断 TPA 介导的保护，而 p38 MAPK 和 PKC delta 抑制剂可阻断应激诱导的神经细胞死亡。 p38 MAPK 失活和 JNK 激活似乎都是 ERK 的下游，因为阻断 ERK 激活的药物也会阻断 TPA 治疗对这些其他 MAP 激酶家族成员的调节。因此，PKC 活性为神经细胞提供免受氧化应激的保护需要多种酶途径的联合调节，这表明 PKC 活性丧失为何会导致神经细胞死亡。
Oxidative stress is implicated in the nerve cell death that occurs in a variety of neurological disorders, and the loss of protein kinase C (PKC) activity has been coupled to the severity of the damage. The functional relationship between stress, PKC, and cell death is, however, unknown. Using an immortalized hippocampal cell line that is particularly sensitive to oxidative stress, I show that activation of PKC by the phorbol ester tetradecanoylphorbol acetate (TPA) inhibits cell death via the stimulation of a complex protein phosphorylation pathway. TPA treatment leads to the rapid activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), the inactivation of p38 mitogen-activated protein kinase (MAPK), and the downregulation of PKC delta. Inhibition of either ERK or JNK activation blocks TPA-mediated protection, whereas p38 MAPK and PKC delta inhibitors block stress-induced nerve cell death. Both p38 MAPK inactivation and JNK activation appear to be downstream of ERK because an agent that blocks ERK activation also blocks the modulation of these other MAP kinase family members by TPA treatment. Thus, the protection from oxidative stress afforded nerve cells by PKC activity requires the combined modulation of multiple enzyme pathways and suggests why the loss of PKC activity contributes to nerve cell death.