ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α
ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α
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DOI：
10.3390/ijms20246309
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Han, Jaeseok
中科院分区：
文献类型：
--
作者：
Lee, Duckgue;Hokinson, Daniel;Han, Jaeseok
内质网（ER）应激影响多种细胞功能，包括细胞周期进程。虽然众所周知内质网应激如何抑制G1期细胞周期的进展，但内质网应激如何诱导G2/M细胞周期阻滞的分子机制仍然很大程度上未知。在这项研究中，我们发现内质网应激和随后的UPR诱导通过减少细胞周期蛋白B1的数量导致细胞周期阻滞在G2/M期。IRE1 α或ATF6 α信号的药理抑制不影响内质网应激诱导的G2/M期细胞周期阻滞。然而，当真核生物翻译起始因子2 （eIF2 α）磷酸化的α亚基被遗传取消时，内质网应激后细胞周期在G2/M期没有停止。GEO数据库分析显示，生长阻滞和dna损伤诱导蛋白α (Gadd45 α)以eIF2a磷酸化依赖的方式诱导，这在本研究中得到了证实。GADD45 α的敲除消除了内质网应激下细胞在G2/M期的周期阻滞。最后，当GADD45 α表达下调时，内质网应激引起的细胞死亡显著减少。综上所述，GADD45 α通过eIF2 α信号通路调控G2/M转化和细胞死亡，是内质网应激诱导的生长停滞的关键介质。
Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1 alpha or ATF6 alpha signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein alpha (Gadd45 alpha) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45 alpha abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45 alpha expression was knocked down. In conclusion, GADD45 alpha is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2 alpha signaling pathway.