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Activating transcription factor 6 (ATF6) negatively regulates Polo-like kinase 4 expression via recruiting C/EBPβ to the upstream-promoter during ER stress.

在ER胁迫过程中,一种c通过将c/ebp β 重新c到上游启动子,激活反式c fa C tor 6 (ATF6) 负调控Polo样激酶 4 的表达。

  • 影响因子:4.62
  • DOI:10.1016/j.bbagrm.2020.194488
  • 作者列表:"Shen T","Li Y","Chen Z","Liang S","Qiu Y","Zhu L","Ba G","Lu G","Qiu L
  • 发表时间:2020-02-01
Abstract

:Polo-like kinase 4 (PLK4) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. However, the alteration of PLK4 in response to endoplasmic reticulum (ER) stress has not been well described. In the present study, we focused on the regulation of PLK4 regulation in response to ER stress. PLK4 expression was dramatically reduced under ER stress induced by brefeldin A (BFA), tunicamycin (TM), or thapsigargin (TG) and down regulation of PLK4 expression was dependent on activating transcription factor 6 (ATF6) and CCAAT/enhancer-binding protein β (C/EBPβ). Luciferase activity analysis of the truncated PLK4 promoter indicated that region from -1343 to -1250 of the PLK4 promoter was sensitive to BFA or TG. Additionally, ChIP and ChIP Re-IP assays showed that ATF6 and C/EBPβ were assembled on the same region of Plk4 promoter. Notably, we identified one C/EBPβ responsive element at position -1284, to which ATF6 or C/EBPβ binding was enhanced by BFA or TG under in vitro and in vivo conditions. Finally, overexpression of PLK4 inhibits apoptosis and promotes cell proliferation in response to ER stress. In summary, these results demonstrated that ER stress plays a crucial role in PLK4 expression. ATF6 may upregulate DNA-binding affinities after BFA treatment, via recruiting C/EBPβ to the upstream promoter of PLK4. These findings may contribute to the understanding of the molecular mechanism of PLK4 regulation.

摘要

: Polo样激酶 4 (PLK4) 是丝氨酸/苏氨酸蛋白激酶家族的一员,参与细胞周期调控和细胞对应激的反应。然而,PLK4 在内质网 (ER) 应激下的变化尚未得到很好的描述。在本研究中,我们重点关注PLK4 在内质网应激反应中的调控。PLK4 在brefeldin A (BFA) 、衣霉素 (TM) 或thapsigargin (TG) 诱导的内质网应激下表达显著降低PLK4 表达下调依赖于激活转录因子 6 (ATF6) 和CCAAT/增强子结合蛋白 β (C/ebp β)。截短的PLK4 启动子的荧光素酶活性分析表明,PLK4 启动子的-1343 至-1250 区域对BFA或TG敏感。此外,ChIP和ChIP Re-IP检测显示ATF6 和C/ebp β 组装在Plk4 启动子的同一区域。值得注意的是,我们在-1284 位确定了一个C/ebp β 反应元件,在体外和体内条件下,BFA或TG增强了与该元件的ATF6 或C/ebp β 结合。最后,PLK4 的过表达抑制细胞凋亡,促进细胞增殖以应对ER应激。总之,这些结果证明ER应激在PLK4 表达中起着至关重要的作用。ATF6 可以通过招募C/ebp β 到plk4 的上游启动子,在BFA处理后上调DNA结合亲和力。这些发现可能有助于了解PLK4 调控的分子机制。

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发表时间:2020-03-01
DOI:10.1177/1078155219842277
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