MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells.
MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells.
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DOI：
10.1016/j.bbamcr.2014.12.013
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发表时间：
2015-03
影响因子：
5.1
通讯作者：
Kilberg, Michael S.
中科院分区：
文献类型：
--
作者：
Shan, Jixiu;Donelan, William;Hayner, Jaclyn N.;Zhang, Fan;Dudenhausen, Elizabeth E.;Kilberg, Michael S.
哺乳动物细胞中的氨基酸（AA）剥夺激活称为AA反应（AAR）的信号级联的集合，其特征在于应激相关基因的转录诱导，包括FBJ鼠骨肉瘤病毒癌基因同源物（cFOS）。本研究证实，HepG 2人肝癌细胞中cFOS基因AA依赖性转录调控的信号传导机制不依赖于经典的GCN 2-eIF 2-ATF 4通路。相反，RAS-RAF-MEK-ERK级联介导AAR信号传导至cFOS基因。在AAR激活后4-24小时观察到cFOS转录增加，与由众所周知的血清应答触发的快速和短暂增加几乎没有重叠。此外，cFOS基因的AA反应性不需要血清，并且没有观察到启动子结合的血清反应因子（SRF）的磷酸化。ERK磷酸化的转录因子E-twenty six-like（p-ELK 1）在AAR激活后与cFOS启动子的结合增加。这项研究确定cFOS是AAR的靶点，并进一步强调了AA响应性MAPK信号在HepG 2细胞中的重要性。
Amino acid (AA) deprivation in mammalian cells activates a collection of signaling cascades known as the AA response (AAR), which is characterized by transcriptional induction of stress-related genes, including FBJ murine osteosarcoma viral oncogene homolog (cFOS). The present study established that the signaling mechanism underlying the AA-dependent transcriptional regulation of the cFOS gene in HepG2 human hepatocellular carcinoma cells is independent of the classic GCN2-eIF2-ATF4 pathway. Instead, a RAS-RAF-MEK-ERK cascade mediates AAR signaling to the cFOS gene. Increased cFOS transcription is observed from 4-24 h after AAR-activation, exhibiting little or no overlap with the rapid and transient increase triggered by the well-known serum response. Furthermore, serum is not required for the AA-responsiveness of the cFOS gene and no phosphorylation of promoter-bound serum response factor (SRF) is observed. The ERK-phosphorylated transcription factor E-twenty six-like (p-ELK1) is increased in its association with the cFOS promoter after activation of the AAR. This research identified cFOS as a target of the AAR and further highlights the importance of AA-responsive MAPK signaling in HepG2 cells.
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