ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2 alpha Phosphorylation and GADD45 alpha

Abstract

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.