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Abstract：
Programmed cell death 4 protein (PDCD4) regulates many vital cell processes, although is classified as a tumor suppressor because it inhibits neoplastic transformation and tumor growth. For example, PCDC4 has been implicated in the regulation of transcription and mRNA translation. PDCD4 is known to inhibit translation initiation by binding to eukaryotic initiation factor 4A and elongation of oncogenic c- and A-myb mRNAs. Additionally, PDCD4 has been shown to interact with poly(A)-binding protein (PABP), which affects translation termination, although the significance of this interaction is not fully understood. Considering the interaction between PABP and PDCD4, we hypothesized that PDCD4 may also be involved in translation termination. Using in vitro translation systems, we revealed that PDCD4 directly activates translation termination. PDCD4 stimulates peptidyl-tRNA hydrolysis induced by a complex of eukaryotic release factors, eRF1-eRF3. Moreover, in combination with the PABP, which also stimulates peptide release, PDCD4 activity in translation termination increases. PDCD4 regulates translation termination by facilitating the binding of release factors to the ribosome, increasing the GTPase activity of eRF3, and dissociating eRF3 from the posttermination complex. Using a toe-printing assay, we determined the first stage at which PDCD4 functions-binding of release factors to the A-site of the ribosome. However, preventing binding of eRF3 with PABP, PDCD4 suppresses subsequent rounds of translation termination. Based on these data, we assumed that human PDCD4 controls protein synthesis during translation termination. The described mechanism of the activity of PDCD4 in translation termination provides a new insight into its functioning during suppression of protein biosynthesis.
摘要：
程序性细胞死亡4蛋白（PDCD4）调节许多重要的细胞过程，虽然被归类为肿瘤抑制剂，因为它抑制肿瘤转化和肿瘤生长。例如,PCDC4与转录和mRNA翻译的调节有关。已知PDCD4通过结合真核细胞起始因子4A和致癌c-和A-mybmRNA的延伸来抑制翻译起始。此外,PDCD4已被证明与poly（A）结合蛋白（PABP）相互作用，影响翻译终止，尽管这种相互作用的意义尚未完全理解。考虑到PABP和PDCD4之间的相互作用，我们假设PDCD4也可能参与翻译终止。使用体外翻译系统，我们发现PDCD4直接激活翻译终止。PDCD4刺激由真核释放因子复合物诱导的肽基-tRNA水解，eRF1-eRF3。此外，结合PABP,这也刺激了肽的释放，翻译终止中的PDCD4活性增加。PDCD4通过促进释放因子与核糖体的结合来调节翻译终止，增加eRF3的GTP酶活性，并从终止后复合物中解离eRF3。使用脚趾打印测定法，我们确定了PDCD4发挥功能的第一阶段-释放因子与核糖体A位点的结合。然而,防止eRF3与PABP结合，PDCD4抑制随后的翻译终止轮。基于这些数据,我们假设人PDCD4在翻译终止过程中控制蛋白质合成.所描述的PDCD4在翻译终止中的活性机制为其在蛋白质生物合成抑制期间的功能提供了新的见解。
