a Laboratory of Molecular Oncogenetics , Institute of Gene Biology, Russian Academy of Sciences , Moscow , Russia.
Cell Cycle. 2017 Oct 2;16(19):1761-1764. doi: 10.1080/15384101.2017.1371881. Epub 2017 Aug 30.
Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap-dependent translation from mRNAs with highly structured 5'-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved. Here we showed that eIF4A1, the eIF4A isoform involved in translation, significantly over-represents Pdcd4 both in cancerous and normal cells. This observation excludes the possibility that cytoplasmic Pdcd4 can efficiently exert its translation suppression function owing to excess of eIF4A, with Pdcd4-free eIF4A being in excess over Pdcd4-bound translation-incompetent eIF4A, thus leaving translation from Pdcd4 mRNA targets unaffected. This contradiction is resumed in the proposed model, which supposes initial complexing between Pdcd4 and its target mRNAs in the nucleus, with subsequent transport of translation-incompetent, Pdcd4-bound target mRNAs into the cytoplasm. Noteworthy, loss of nuclear Pdcd4 in cancer cells was reported to correlate with tumor progression, which supports the proposed model of Pdcd4 functioning.
程序性细胞死亡因子 4（Pdcd4）在各种起源的肿瘤中经常受到抑制，其抑制与肿瘤进展相关。Pdcd4 通过与真核翻译起始因子 4A（eIF4A）解旋酶和靶转录本相互作用，抑制具有高度结构化 5'-区的 mRNA 的帽依赖性翻译。Pdcd4 蛋白的减少被认为提供了对其他受抑制的 eIF4A 依赖性翻译蛋白的缓解，从而促进肿瘤进展。然而，目前尚不清楚细胞中 Pdcd4 水平的降低是否足以通过出现无 Pdcd4 的翻译活性 eIF4A 蛋白来缓解翻译抑制，或者涉及更复杂和选择性的机制。在这里，我们表明，eIF4A1，参与翻译的 eIF4A 同工型，在癌细胞和正常细胞中均显著过表达 Pdcd4。这一观察结果排除了细胞质 Pdcd4 由于 eIF4A 过量而能够有效地发挥其翻译抑制功能的可能性，无 Pdcd4 的 eIF4A 过量于 Pdcd4 结合的翻译失活的 eIF4A，从而使 Pdcd4 mRNA 靶标不受翻译影响。这一矛盾在提出的模型中得到了总结，该模型假设 Pdcd4 与其靶 mRNA 最初在核内复合，随后将无翻译活性的、Pdcd4 结合的靶 mRNA 转运到细胞质中。值得注意的是，癌细胞中核内 Pdcd4 的丢失与肿瘤进展相关，这支持了 Pdcd4 功能的提出模型。
