Scoumanne A, Zhang J, Chen X
Center for Comparative Oncology, University of California at Davis, CA 95616, USA.
Nucleic Acids Res. 2009 Aug;37(15):4965-76. doi: 10.1093/nar/gkp516. Epub 2009 Jun 15.
Protein arginine methyltransferases (PRMTs) mediate the transfer of methyl groups to arginines in proteins involved in signal transduction, transcriptional regulation and RNA processing. Tumor suppressor p53 coordinates crucial cellular processes, including cell-cycle arrest and DNA repair, in response to stress signals. Post-translational modifications and interactions with co-factors are important to regulate p53 transcriptional activity. To explore whether PRMTs modulate p53 function, we generated multiple cell lines in which PRMT1, CARM1 and PRMT5 are inducibly knocked down. Here, we showed that PRMT5, but not PRMT1 or CARM1, is essential for cell proliferation and PRMT5 deficiency triggers cell-cycle arrest in G1. In addition, PRMT5 is required for p53 expression and induction of p53 targets MDM2 and p21 upon DNA damage. Importantly, we established that PRMT5 knockdown prevents p53 protein synthesis. Furthermore, we found that PRMT5 regulates the expression of translation initiation factor eIF4E and growth suppression mediated upon PRMT5 knockdown is independent of p53 but is dependent on eIF4E. Taken together, we uncovered that arginine methyltransferase PRMT5 is a major pro-survival factor regulating eIF4E expression and p53 translation.
蛋白质精氨酸甲基转移酶（PRMTs）介导甲基基团转移至参与信号转导、转录调控和RNA加工的蛋白质中的精氨酸上。肿瘤抑制因子p53可响应应激信号协调关键的细胞过程，包括细胞周期停滞和DNA修复。翻译后修饰以及与辅因子的相互作用对于调节p53的转录活性很重要。为了探究PRMTs是否调节p53功能，我们构建了多个可诱导敲低PRMT1、CARM1和PRMT5的细胞系。在此，我们表明PRMT5而非PRMT1或CARM1对细胞增殖至关重要，且PRMT5缺陷会引发G1期细胞周期停滞。此外，PRMT5是DNA损伤时p53表达以及p53靶标MDM2和p21诱导所必需的。重要的是，我们证实敲低PRMT5可阻止p53蛋白合成。此外，我们发现PRMT5调节翻译起始因子eIF4E的表达，且敲低PRMT5介导的生长抑制不依赖于p53，但依赖于eIF4E。综上所述，我们发现精氨酸甲基转移酶PRMT5是调节eIF4E表达和p53翻译的主要促生存因子。
