Extracellular signal-regulated kinase (ERK) activity is required for TPA-mediated inhibition of drug-induced apoptosis.
Extracellular signal-regulated kinase (ERK) activity is required for TPA-mediated inhibition of drug-induced apoptosis.
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TPA 介导的药物诱导细胞凋亡抑制需要细胞外信号调节激酶 (ERK) 活性。
DOI：
10.1006/bbrc.1998.8410
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发表时间：
1998
影响因子：
3.1
通讯作者：
Kucera,GL
中科院分区：
文献类型：
--
作者：
Stadheim,TA;Kucera,GL
白血病细胞对毒性刺激的反应是经历一种称为凋亡的程序性细胞死亡。然而，负责执行这种形式的死亡的信号事件知之甚少。丝裂原活化蛋白激酶（MAPK）信号级联参与细胞对细胞外刺激的应答。具体而言，细胞外信号调节激酶（ERK）与增殖和分化相关，而c-Jun N-末端激酶/应激激活蛋白激酶（JNK/SAPKs）与细胞停滞和死亡有关。我们报道了12-O-十四酰基佛波醇-13-乙酸酯（TPA）在抑制JNK/SAPK激活剂茴香霉素刺激的HL-60细胞凋亡中的作用。这种抗凋亡作用伴随着ERK活性的持续增加。此外，蛋白激酶C（PKC）抑制剂的使用表明，PKC参与诱导ERK活性和TPA的细胞凋亡的抑制，因为当细胞用PKC抑制剂预处理时，细胞凋亡的抑制减弱。最后，我们观察到使用MEK 1抑制剂PD 98059抑制TPA介导的ERK活性并消除TPA的抗凋亡作用。然而，凋亡抑制并不完全依赖于ERK，因为缺乏JNK/SAPK刺激的细胞不发生凋亡。因此，我们得出结论，TPA抑制诱导的凋亡在茴香霉素处理的HL-60细胞通过ERK依赖的途径，这种效果可以逆转ERK活性的衰减伴随着JNK/SAPK活性的刺激。
Leukemia cells respond to toxic stimuli by undergoing a form of programmed cell death known as apoptosis. However, the signaling events responsible for the execution of this form of death are poorly understood. Mitogen-activated protein kinase (MAPK) signaling cascades are involved in the cellular response to extracellular stimuli. Specifically, extracellular signal-regulated kinases (ERKs) have been associated with proliferation and differentiation, whereas the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs) have been implicated in cell arrest and death. We report the use of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the inhibition of apoptosis in HL-60 cells stimulated with the JNK/SAPK activator anisomycin. This anti-apoptotic effect was accompanied by a sustained increase in ERK activity. Furthermore, the use of protein kinase C (PKC) inhibitors suggested that PKC was involved in the induction of ERK activity and in the inhibition of apoptosis by TPA since the inhibition of apoptosis was attenuated when cells were pretreated with PKC inhibitors. Lastly, we observed that the use of the MEK1 inhibitor PD98059 inhibited TPA-mediated ERK activity and abrogated the anti-apoptotic effects of TPA. However, apoptotic inhibition was not solely ERK-dependent since cells lacking JNK/SAPK stimulation did not undergo apoptosis. Therefore, we conclude that TPA inhibits the induction of apoptosis in anisomycin-treated HL-60 cells through an ERK-dependent pathway and that this effect can be reversed by the attenuation of ERK activity accompanied with the stimulation of JNK/SAPK activity.