Leśniczak-Staszak Marta, Pietras Paulina, Ruciński Marcin, Johnston Ryan, Sowiński Mateusz, Andrzejewska Małgorzata, Nowicki Michał, Gowin Ewelina, Lyons Shawn M, Ivanov Pavel, Szaflarski Witold
Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań 60-781, Poland.
Department of Biochemistry and Cell Biology, Boston University School of Medicine, Boston, MA 02118, USA.
J Cell Sci. 2024 Jun 15;137(12). doi: 10.1242/jcs.261825. Epub 2024 Jun 28.
Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.
一些化疗药物可调节应激颗粒（SGs）的形成，应激颗粒是含有RNA的细胞质病灶，参与应激反应途径。应激颗粒如何在机制上促进细胞存活或凋亡功能，这一点必须得到更明确的界定。化疗药物洛莫司汀通过激活应激感应eIF2α激酶HRI（由EIF2AK1基因编码）来促进应激颗粒的形成。在此，我们应用基于DNA微阵列的转录组分析来确定受洛莫司汀诱导的应激调节的基因，并揭示应激颗粒在此过程中的作用。我们发现，促凋亡EGR1基因的表达在洛莫司汀处理后的细胞中受到特异性调节。编码EGR1的mRNA出现在应激颗粒中，这与EGR1 mRNA翻译的减少相关。具体而言，洛莫司汀处理后，EGR1 mRNA被隔离到应激颗粒中，可能阻止其核糖体翻译，从而限制细胞凋亡的程度。我们的数据支持这样一种模型，即应激颗粒可以以应激特异性的方式选择性地隔离特定的mRNA，调节其翻译可用性，从而决定应激细胞的命运。
