Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3β in the regulation of HSF-1 activity
Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3β in the regulation of HSF-1 activity
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DOI：
10.1046/j.1471-4159.2000.0752401.x
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发表时间：
2000-12-01
影响因子：
4.7
通讯作者：
Jope, RS
中科院分区：
文献类型：
--
作者：
Bijur, GN;Jope, RS
升高的温度激活存活启动子Akt和热休克因子-1（HSF-1），热休克因子-1是一种诱导热休克蛋白（HSP）（如HSP-70）表达的转录因子。由于控制这些反应的神经元机制尚不清楚，因此在人神经母细胞瘤SH-SY 5 Y细胞中研究了这些。热休克（45 ℃）迅速激活Akt、细胞外信号调节激酶1和2（ERK 1/2）和p38，但只有Akt以磷脂酰肌醇3-激酶（PI-3 K）依赖性方式激活，因为PI-3 K抑制剂LY 294002和渥曼青霉素阻断Akt激活，但不阻断ERK 1/2或p38激活。Akt的激活没有被p38或ERK 1/2的抑制所阻断，表明这些信号系统的独立性。热休克处理也引起HSF-1 DNA结合活性的快速增加，这部分依赖于PI-3 K活性，因为两种PI-3 K抑制剂都减弱了这种反应。因为Akt抑制糖原合成酶激酶-3 β（GSK-3 β），一种促进细胞死亡的酶，我们测试GSK-3 β是否是HSF-1活化的负调节剂。GSK-3 β的过表达损害热休克诱导的HSF-1活化，并且还减少HSP-70的产生，这被GSK-3 β抑制剂锂部分恢复。因此，热休克诱导的PI-3 K活化和GSK-3 β对HSF-1活化和HSP-70表达的抑制作用意味着Akt诱导的GSK-3 β抑制有助于HSF-1的活化。
Elevated temperatures activate the survival promoters Akt and heat shock factor-1 (HSF-1), a transcription factor that induces the expression of heat shock proteins (HSPs), such as HSP-70, Because neuronal mechanisms controlling these responses are not known, these were investigated in human neuroblastoma SH-SY5Y cells. Heat shock (45 degreesC) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (PI-3K)-dependent manner, as the PI-3K inhibitors LY294002 and wortmannin blocked Akt activation, but not ERK1/2 or p38 activation. Akt activation was not blocked by inhibition of p38 or ERK1/2, indicating the independence of these signaling systems. Heat shock treatment also caused a rapid increase in HSF-1 DNA binding activity that was partially dependent on PI-3K activity, as both the PI-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3 beta (GSK-3 beta), an enzyme that facilitates cell death, we tested if GSK-3 beta is a negative regulator of HSF-1 activation, Overexpression of GSK-3 beta impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3 beta inhibitor lithium. Thus, heat shock-induced activation of PI-3K and the inhibitory effect of GSK-3 beta on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3 beta contributes to the activation of HSF-1.