ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α
Autor: | Daniel Hokinson, Seok-Geun Lee, So-Young Park, Duckgue Lee, Rosalie Elvira, Jaeseok Han, Fedho Kusuma, Miyong Yun, Ji-Min Lee |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Programmed cell death Cell cycle checkpoint Eukaryotic Initiation Factor-2 Cell Cycle Proteins Catalysis Article Inorganic Chemistry 03 medical and health sciences 0302 clinical medicine Databases Genetic Humans Physical and Theoretical Chemistry Cyclin B1 Phosphorylation eIF2α phosphorylation Molecular Biology G2-M cell cycle arrest Spectroscopy G alpha subunit Chemistry Endoplasmic reticulum Organic Chemistry General Medicine Cell cycle Endoplasmic Reticulum Stress Computer Science Applications Cell biology G2 Phase Cell Cycle Checkpoints 030104 developmental biology cell death 030220 oncology & carcinogenesis Unfolded protein response GADD45α Signal transduction ER stress Cell Division Signal Transduction |
Zdroj: | International Journal of Molecular Sciences Volume 20 Issue 24 |
ISSN: | 1422-0067 |
Popis: | 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. |
Databáze: | OpenAIRE |
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