Insulin-regulated expression of Egr-1 and Krox20: Dependence on ERK1/2 and interaction with p38 and PI3-kinase pathways
Insulin-regulated expression of Egr-1 and Krox20: Dependence on ERK1/2 and interaction with p38 and PI3-kinase pathways
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DOI：
10.1210/en.2003-0592
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发表时间：
2003-12-01
期刊：
影响因子：
4.8
通讯作者：
Messina, JL
中科院分区：
文献类型：
--
作者：
Keeton, AB;Bortoff, KD;Messina, JL
除了其快速改变代谢的能力之外，胰岛素还能够通过激活PI 3-激酶（PI 3-K）、MAPK激酶（MEK）-ERK或p38途径来调节许多基因的表达。利用H4 IIE细胞的差异筛选，我们已经确定了早期反应基因Egr锌指转录因子家族的两个成员，Egr-1和Krox 20，其转录由胰岛素治疗诱导。Egr-1可能参与胰岛素对肝脏基因表达的调控。Krox 20的调节和表达主要在神经细胞和组织中进行研究，但以前很少报道Krox 20在肝源性细胞中的存在或其受胰岛素的调节。在目前的研究中，胰岛素治疗迅速增加Egr-1和Krox 20的转录。在用PI 3-K抑制剂预处理的细胞中，胰岛素对Egr-1和Krox 20的作用没有减少，但Egr-1转录增加。ERK 1/2磷酸化的快速诱导被MEK 1抑制剂预处理完全阻断，并且与胰岛素刺激的Egr-1和Krox 20的诱导几乎完全抑制相关，表明该途径是胰岛素对这些基因的作用所必需的。最后，抑制p38通路，然后加入胰岛素，引起Egr-1和Krox 20的叠加诱导。总之，这些基因通过MEK-ERK和p38途径的协调调节被胰岛素诱导，在Egr-1的情况下，通过PI 3-K途径。
In addition to its ability to rapidly alter metabolism, insulin is also able to regulate the expression of numerous genes via activation of the PI3-kinase (PI3-K), MAPK kinase (MEK)-ERK,or p38 pathways. Using differential screening of H4IIE cells, we have identified two members of the Egr zinc-finger transcription factor family of early response genes, Egr-1 and Krox20, whose transcription is induced by insulin treatment. Egr-1 may be involved in insulin's regulation of hepatic gene expression. Krox20 regulation and expression have been primarily studied in neural cells and tissues, but little has been previously reported on the presence of Krox20 in cells of hepatic origin or its regulation by insulin. In the present studies, insulin treatment rapidly increased transcription of both Egr-1 and Krox20. In cells pretreated with a PI3-K inhibitor, there was no reduction in the effect of insulin on Egr-1 and Krox20, but an increase in Egr-1 transcription. The rapid induction of ERK1/2 phosphorylation was completely blocked by pretreatment with a MEK1 inhibitor and was associated with a nearly complete inhibition of insulin-stimulated induction of both Egr-1and Krox20, indicating this pathway is necessary for insulin's effect on these genes. Finally, inhibition of the p38 pathway, followed by insulin addition, caused an additive induction of both Egr-1and Krox20. In conclusion, these genes are induced by insulin via coordinated regulation of the MEK-ERK and p38 pathways and, in the case of Egr-1, the PI3-K pathway.