The duration of ERK 1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1
The duration of ERK 1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1
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DOI：
10.1016/j.cellsig.2006.09.001
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发表时间：
2007-04-01
影响因子：
4.8
通讯作者：
Cook, Simon J.
中科院分区：
文献类型：
--
作者：
Chalmers, Claire J.;Gilley, Rebecca;Cook, Simon J.
ERK 1/2激活的持续时间影响对激动剂的生物反应的性质。AP-1转录因子家族的成员是ERK 1/2通路的众所周知的靶标，并且在细胞周期再进入期间以时间协调的方式表达。在CC 139成纤维细胞中，持续的ERK 1/2激活是Fra-1、Fra-2、c-Jun和JunB表达所必需的，而c-Fos的表达即使在对瞬时ERK激活的响应中仍然被强烈诱导。然而，这种表达模式对AP-1活性的意义尚未得到解决。在这里，我们表明，生长因子刺激的C-末端c-Fos反式激活结构域（c-Fos）的激活作为ERK 1/2信号持续时间的传感器，而c-Junkline是不响应生长因子。此外，持续的ERK 1/2激活决定了AP-1 DNA结合复合物增加的持续时间以及它们的定性组成。最后，这反映在稳定整合的AP-1报告构建体的持续时间和定量转录输出中，表明AP-1活性与ERK 1/2信号持续时间微调。这些结果为ERK 1/2信号持续时间在AP-1调控中的重要性提供了新的见解，并为信号持续时间的差异如何导致基因表达的定量和定性变化提供了解释。(c)2006年爱思唯尔公司All rights reserved.
The duration of ERK 1/2 activation influences the nature of the biological response to agonist. Members of the AP-1 transcription factor family are well known targets of the ERK1/2 pathway and are expressed in a temporally coordinated fashion during cell cycle re-entry. In CC139 fibroblasts, sustained ERK1/2 activation is required for the expression of Fra-1, Fra-2, c-Jun and JunB, whereas expression of c-Fos is still strongly induced even in response to transient ERK activation. However, the significance of this pattern of expression for AP-1 activity has not been addressed. Here we show that growth factor stimulated activation of the C-terminal c-Fos transactivation domain (TAD) serves as a sensor for ERK1/2 signal duration whereas the c-JunTAD is not responsive to growth factors. In addition, sustained ERK1/2 activation determines the duration of increases in AP-1 DNA binding complexes as well as their qualitative make up. Finally, this is reflected in both the duration and quantitative transcriptional output of stably integrated AP-1 reporter constructs, indicating that AP-1 activity is finely tuned to ERK1/2 signal duration. These results provide new insights into the importance of ERK 1/2 signal duration in the regulation of AP-1 and provide an explanation for how differences in signal duration can lead to both quantitative and qualitative changes in gene expression. (c) 2006 Elsevier Inc. All rights reserved.