A novel eIF5A complex functions as a regulator of p53 and p53-dependent apoptosis
A novel eIF5A complex functions as a regulator of p53 and p53-dependent apoptosis
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DOI：
10.1074/jbc.m407165200
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发表时间：
2004-11-19
影响因子：
4.8
通讯作者：
Zhang, XM
中科院分区：
文献类型：
--
作者：
Li, AL;Li, HY;Zhang, XM
虽然真核生物翻译起始因子5A （eIF5A）最初被指定为“起始因子”，但最近的数据表明它也参与细胞凋亡。然而，eIF5A在细胞凋亡中的实际作用尚不清楚。在这项研究中，我们通过酵母双杂交筛选来鉴定eIF5A相互作用蛋白，以帮助我们了解eIF5A的机制。我们的研究结果表明，eIF5A和syntenin在体外和体内都可以参与特定的相互作用，并协同调节p53的活性。我们的发现首次揭示了eIF5A作为p53调节因子的一种新的生物活性。过表达eIF5A或其EFP结构域导致p53上调，通过小干扰RNA沉默eIF5A可降低p53蛋白水平。进一步的反转录PCR分析显示eif5a激活p53转录。eIF5A对p53转录活性的影响进一步通过p53已知靶基因p21和Bax的表达增加得到证实。相反，eIF5A的一个点突变体，假设被取消，被发现在p53上调中存在功能缺陷。过度表达eIF5A导致p53依赖性细胞凋亡或致敏细胞被化疗药物诱导凋亡。然而，当eIF5A与其新伙伴syntenin相互作用时，eIF5A诱导的p53蛋白水平升高被显著抑制。因此，eIF5A似乎是一种之前未被识别的p53调节因子，可能为p53依赖性细胞凋亡定义了一条新的途径，syntenin可能通过平衡eIF5A对p53信号的调节来调节p53的凋亡。
Although eukaryotic translation initiation factor 5A (eIF5A) was originally designated as an "initiation factor," recent data have shown it to be also involved in apoptosis. However, the actual function of eIF5A in apoptosis is still unknown. In this study, we performed yeast two-hybrid screens to identify eIF5A-interacting proteins to help us understand the mechanisms of eIF5A. Our results demonstrated that eIF5A and syntenin could engage in a specific interaction both in vitro and in vivo and functioned collaboratively to regulate p53 activity. Our findings, for the first time, revealed a new biological activity for eIF5A as the regulator of p53. Overexpression of eIF5A or its EFP domain resulted in up-regulation of p53, and silencing eIF5A by small interfering RNA reduced the p53 protein level. Further analysis by reverse transcription PCR showed eIF5A-activated p53 transcription. The effect of eIF5A on p53 transcriptional activity was further demonstrated by the increasing expressions of p21 and Bax, well known target genes of p53. In contrast, a point mutant of eIF5A, hypusination being abolished, was revealed to be functionally defective in p53 up-regulation. Overexpression of eIF5A led to a p53-dependent apoptosis or sensitized cells to induction of apoptosis by chemotherapeutic agents. However, when eIF5A interacted with its novel partner, syntenin, the eIF5A-induced increase in p53 protein level was significantly inhibited. Therefore, eIF5A seems to be a previously unrecognized regulator of p53 that may define a new pathway for p53-dependent apoptosis, and syntenin might regulate p53 by balancing the regulation of eIF5A signaling to p53 for apoptosis.