Department of Biology, Kyung Hee University, Seoul, 02447, Korea.
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Korea.
Sci Rep. 2017 Aug 29;7(1):9816. doi: 10.1038/s41598-017-10358-2.
eIF4E is an initiator protein in cap-dependent translation. Its overexpression is linked to tumorigenesis in various human cancers, suggesting that the levels of eIF4E must be under tight control in normal cells. Although several eIF4E regulatory mechanisms have been demonstrated, the intracellular mechanisms controlling eIF4E protein levels remain poorly understood. Here, we report that eIF4E is efficiently regulated by dual mechanisms, both involving human inhibitor of apoptosis family protein cIAP1. cIAP1 itself ubiquitinates eIF4E as an E3 ligase, and interestingly, cIAP1 also functions as a mediator to present eIF4E to another E3 ligase, CHIP. This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis. Our results provide the first evidence for a mediator function of cIAP1 and collaborative activity of cIAP1 and CHIP, suggesting that maintaining balanced levels of these E3 ligases might be beneficial for normal cell growth.
eIF4E 是一种帽依赖性翻译的起始蛋白。其过度表达与多种人类癌症的肿瘤发生有关，这表明 eIF4E 的水平必须在正常细胞中受到严格控制。尽管已经证明了几种 eIF4E 调节机制，但控制 eIF4E 蛋白水平的细胞内机制仍知之甚少。在这里，我们报告 eIF4E 受到双重机制的有效调节，这两种机制都涉及到人类凋亡抑制蛋白家族蛋白 cIAP1。cIAP1 本身作为 E3 连接酶泛素化 eIF4E，有趣的是，cIAP1 还作为一种介质将 eIF4E 呈现给另一种 E3 连接酶 CHIP。cIAP1 和 CHIP 的这种协作活性将 eIF4E 导向降解，控制其水平并抑制肿瘤发生。我们的结果为 cIAP1 的介质功能和 cIAP1 和 CHIP 的协作活性提供了第一个证据，这表明维持这些 E3 连接酶的平衡水平可能有利于正常细胞生长。
