Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China.
Mol Cell Biol. 2020 Nov 20;40(24). doi: 10.1128/MCB.00302-20.
WD repeat domain 77 protein (WDR77) is required for cellular proliferation of lung and prostate epithelial cells during earlier stages of development and is reactivated during prostate and lung tumorigenesis. WDR77 plays an essential role in prostate tumorigenesis and cell growth mediated by growth regulatory factors. Here, we identified E2F1 and E2F3 mRNAs as translational targets of WDR77. We demonstrated that WDR77 regulated the translation of E2F1 and E2F3 mRNAs through the 5' untranslated regions (UTRs) of E2F1 and E2F3 (E2F1/3) mRNAs. WDR77 physically interacted with programmed cell death 4 (PDCD4) that suppresses translation of mRNAs containing structured 5' UTRs by interacting with eukaryotic translation initiation factor 4A (eIF4A) and inhibiting its helicase activity. Further, we demonstrated that the interaction between WDR77 and PDCD4 prevented the binding of PDCD4 to eIF4A and relieved PDCD4's inhibitory effect on eIF4A1. Overall, our work reveals for the first time that WDR77 is directly involved in translational regulation of E2F1/3 mRNAs through their structured 5' UTRs, PDCD4, and eIF4A1 and provides novel insight into the cell growth controlled by WDR77.
WD 重复结构域 77 蛋白（WDR77）在肺和前列腺上皮细胞发育早期的细胞增殖中是必需的，并且在前列腺和肺癌发生过程中被重新激活。WDR77 在前列腺肿瘤发生和生长调节因子介导的细胞生长中发挥重要作用。在这里，我们鉴定了 E2F1 和 E2F3 mRNA 作为 WDR77 的翻译靶标。我们证明 WDR77 通过 E2F1 和 E2F3（E2F1/3）mRNA 的 5'非翻译区（UTR）调节 E2F1 和 E2F3 mRNA 的翻译。WDR77 与程序性细胞死亡因子 4（PDCD4）相互作用，PDCD4 通过与真核翻译起始因子 4A（eIF4A）相互作用并抑制其解旋酶活性，从而抑制含有结构化 5'UTR 的 mRNA 的翻译。此外，我们证明 WDR77 与 PDCD4 之间的相互作用阻止了 PDCD4 与 eIF4A 的结合，并减轻了 PDCD4 对 eIF4A1 的抑制作用。总的来说，我们的工作首次揭示了 WDR77 通过其结构化 5'UTR、PDCD4 和 eIF4A1 直接参与 E2F1/3 mRNA 的翻译调控，并为 WDR77 控制细胞生长提供了新的见解。
