Sequential actions of ERK1/2 on the AP-1 transcription factor allow temporal integration of metabolic signals in pancreatic β cells
Sequential actions of ERK1/2 on the AP-1 transcription factor allow temporal integration of metabolic signals in pancreatic β cells
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DOI：
10.1096/fj.06-7798com
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Schlegel, Werner
中科院分区：
文献类型：
--
作者：
Glauser, Dominique A.;Schlegel, Werner
由fos和jun基因产物组成的AP-1转录因子介导胰腺β细胞对激素和代谢刺激的转录反应。在这里，我们研究了动态控制AP-1亚基蛋白表达的机制。在MIN6细胞中，葡萄糖和GLP-1以双相动力学升高c-FOS蛋白，最初的峰值随后是一个持续的平台，只要保持刺激。ERK1/2激活与c-FOS表达平行。c-FOS蛋白的初始诱导需要依赖erk1 /2的c-FOS转录激活和从头蛋白合成，而c-FOS在持续刺激下的持续积累则不需要。事实上，依赖于ERK1/2的激活，c-FOS以其过度磷酸化的形式积累，通过蛋白酶体途径保护其不被降解。在大鼠原代β细胞中证实了ERK1/2在c-FOS蛋白积累中的作用，并通过dna结合和报告基因实验证明了这一机制的功能后果。总之，这些发现揭示了ERK1/2对AP-1的顺序调控，它最初增加了c-fos的转录，如果刺激持续，稳定新合成的c-fos蛋白，有效地激活AP-1调控基因的转录。这个ERK1/2-AP-1模块可以作为时间积分器，将不同持续时间的代谢刺激转化为不同的转录输出。
The AP-1 transcription factor composed of fos and jun gene products mediates transcriptional responses to hormonal and metabolic stimulations of pancreatic beta cells. Here, we investigated the mechanisms that dynamically control expression of AP-1 subunit proteins. In MIN6 cells, glucose and GLP-1 raised c-FOS protein with biphasic kinetics, an initial peak being followed by a plateau that persisted as long as stimuli were maintained. ERK1/2 activation paralleled c-FOS expression. Whereas initial induction of c-FOS protein required ERK1/2-dependent activation of c-fos transcription and de novo protein synthesis, persistent accumulation of c-FOS under sustained stimulation did not. Indeed, dependent on ERK1/2 activation, c-FOS accumulated in its hyperphosphorylated form protected from degradation through the proteasome pathway. The implication of ERK1/2 in the accumulation of c-FOS protein was confirmed in rat primary beta cells, and the functional consequences of this mechanism were demonstrated with DNA-binding and reporter assays. Altogether these findings reveal a sequential regulation of AP-1 by ERK1/2, which initially increases transcription of c-fos and, if stimulation persists, stabilizes freshly synthesized c-FOS protein to efficiently activate the transcription of AP-1-regulated genes. This ERK1/2-AP-1 module can function as a temporal integrator converting metabolic stimuli of different durations into differential transcriptional outputs.