Differential control of the CCAAT/enhancer-binding protein β (C/EBPβ) products liver-enriched transcriptional activating protein (LAP) and liver- enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the response to endoplasmic reticulum stress
Differential control of the CCAAT/enhancer-binding protein β (C/EBPβ) products liver-enriched transcriptional activating protein (LAP) and liver- enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the response to endoplasmic reticulum stress
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DOI：
10.1074/jbc.m801046200
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发表时间：
2008-08-15
影响因子：
4.8
通讯作者：
Hatzoglou, Maria
中科院分区：
文献类型：
--
作者：
Li, Yi;Bevilacqua, Elena;Hatzoglou, Maria
内质网（ER）中未折叠蛋白的积累触发了一个应激反应程序，该程序在反应早期保护细胞，并可在长期应激期间导致细胞凋亡。碱性亮氨酸拉链转录因子，CCAAT/增强子结合蛋白β（C/EBP β），是ER应激过程中表达增加的基因之一。来自不同起始密码子的C/EBP β mRNA的翻译导致两种转录激活因子（EBP-1和EBP-2）和一种转录抑制因子（LIP）的合成。LIP/EBP比率是C/EBP β介导的基因转录的关键因素。这里显示，在ER应激的早期阶段，LIP/ER比值降低了5倍，在晚期阶段增加了20倍，主要是因为LIP水平的变化。LIP的早期降低需要通过蛋白酶体途径和翻译起始因子eIF 2 α的磷酸化进行降解。LIP水平在晚期增加是由于蛋白质的合成增加和稳定性增加。有人提出，ER应力过程中的合成和降解速率的调节控制LIP/EDP比。使用C/EBP β缺陷小鼠胚胎成纤维细胞证明了C/EBP β在ER应激反应程序中的重要性。显示C/EBP β减弱晚期ER应激中促存活ATF 4靶基因的表达，并增强CHOP下游的细胞死亡相关基因的表达。证明了LIP对ATF 4诱导的cat-1氨基酸转运蛋白基因转录的抑制作用。我们的结论是，在ER应激过程中的LIP/EIP比值的调节是一种新的机制，用于调节细胞的应激反应。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a stress response program that protects cells early in the response and can lead to apoptosis during prolonged stress. The basic leucine zipper transcription factor, CCAAT/enhancer-binding protein beta (C/EBP beta), is one of the genes with increased expression during ER stress. Translation of the C/EBP beta mRNA from different initiation codons leads to the synthesis of two transcriptional activators (LAP-1 and -2) and a transcriptional repressor (LIP). The LIP/LAP ratio is a critical factor in C/EBP beta-mediated gene transcription. It is shown here that the LIP/LAP ratio decreased by 5-fold during the early phase of ER stress and increased by 20-fold during the late phase, mostly because of changes in LIP levels. The early decrease in LIP required degradation via the proteasome pathway and phosphorylation of the translation initiation factor, eIF2 alpha. The increased LIP levels during the late phase were due to increased synthesis and increased stability of the protein. It is proposed that regulation of synthesis and degradation rates during ER stress controls the LIP/LAP ratio. The importance of C/EBP beta in the ER-stress response program was demonstrated using C/EBP beta-deficient mouse embryonic fibroblasts. It is shown that C/EBP beta attenuates expression of pro-survival ATF4 target genes in late ER stress and enhances expression of cell death-associated genes downstream of CHOP. The inhibitory effect of LIP on ATF4-induced transcription was demonstrated for the cat-1 amino acid transporter gene. We conclude that regulation of LIP/LAP ratios during ER stress is a novel mechanism for modulating the cellular stress response.