Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
Department of Food Bioscience, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
Biochem Biophys Res Commun. 2014 Oct 3;452(4):1016-21. doi: 10.1016/j.bbrc.2014.09.033. Epub 2014 Sep 16.
It is becoming clear that PRMT5 plays essential roles in cell cycle progression, survival, and responses to external stresses. However, the precise mechanisms underlying such roles of PRMT5 have not been clearly understood. Previously, we have demonstrated that PRMT5 participates in cellular adaptation to hypoxia by ensuring 5'-cap dependent translation of HIF-1α. Given that c-Myc and cyclin D1 expressions are also tightly regulated in 5'-cap dependent manner, we here tested the possibility that PRMT5 promotes cell proliferation by increasing de novo syntheses of the oncoproteins. c-Myc and cyclin D1 were found to be noticeably downregulated by PRMT5 knock-down. A RNA immunoprecipitation analysis, which can identify RNA-protein interactions, showed that PRMT5 is required for the interaction among eIF4E and 5'-UTRs of HIF-1α, c-Myc and cyclin D1 mRNAs. In addition, PRMT5 knock-down inhibited cell proliferation by inducing cell cycle arrest at the G1 phase. More importantly, ectopic expression of eIF4E significantly rescued the cell cycle progression and cell proliferation even in PRMT5-deficeint condition. Based on these results, we propose that PRMT5 determines cell fate by regulating 5'-cap dependent translation of proteins essential for proliferation and survival.
越来越多的证据表明 PRMT5 在细胞周期进程、存活和对外界应激的反应中发挥着重要作用。然而，PRMT5 发挥这些作用的确切机制尚未被清楚地理解。先前，我们已经证明 PRMT5 通过确保 HIF-1α 的 5'-帽依赖翻译来参与细胞对缺氧的适应。鉴于 c-Myc 和细胞周期蛋白 D1 的表达也受到严格的 5'-帽依赖调控，我们在这里测试了 PRMT5 通过增加新合成的癌蛋白来促进细胞增殖的可能性。PRMT5 敲低明显下调了 c-Myc 和 cyclin D1 的表达。一种可以鉴定 RNA-蛋白相互作用的 RNA 免疫沉淀分析表明，PRMT5 是 eIF4E 与 HIF-1α、c-Myc 和 cyclin D1 mRNA 的 5'-UTR 之间相互作用所必需的。此外，PRMT5 敲低通过诱导细胞周期停滞在 G1 期来抑制细胞增殖。更重要的是，即使在 PRMT5 缺陷的情况下，eIF4E 的异位表达也显著挽救了细胞周期进程和细胞增殖。基于这些结果，我们提出 PRMT5 通过调节对增殖和存活至关重要的蛋白质的 5'-帽依赖翻译来决定细胞命运。
