The WEE1 regulators CPEB1 and miR-15b switch from inhibitor to activators at G2/M

MicroRNAs (miRNAs) in the AGO-containing RISC complex control messenger RNA (mRNA) translation by binding to mRNA 3′ untranslated region (3′UTR). The relationship between miRNAs and other regulatory factors that also bind to mRNA 3′UTR, such as CPEB1 (cytoplasmic polyadenylation element-binding protein), remains elusive. We found that both CPEB1 and miR-15b control the expression of WEE1, a key mammalian cell cycle regulator. Together, they repress WEE1 protein expression during G1 and S-phase. Interestingly, the 2 factors lose their inhibitory activity at the G2/M transition, at the time of the cell cycle when WEE1 expression is maximal, and, moreover, rather activate <i>WEE1</i> translation in a synergistic manner. Our data show that translational regulation by RISC and CPEB1 is essential in cell cycle control and, most importantly, is coordinated, and can be switched from inhibition to activation during the cell cycle.

含AGO蛋白的RNA诱导沉默复合物（AGO-containing RISC）中的微小RNA（MicroRNAs, miRNAs）可通过结合信使RNA（messenger RNA, mRNA）的3'非翻译区（3′ untranslated region, 3′UTR）调控其翻译过程。目前，微小RNA与其他同样结合mRNA 3'非翻译区的调控因子（如胞质多聚腺苷酸化元件结合蛋白1，CPEB1, cytoplasmic polyadenylation element-binding protein）之间的调控关系仍未阐明。本研究发现，CPEB1与miR-15b均可调控哺乳动物细胞周期关键调控因子WEE1的表达；二者协同可在细胞周期G1期与S期抑制WEE1的蛋白表达。有趣的是，在细胞周期WEE1表达水平最高的G2/M期转换节点，这两种因子会丧失其抑制活性，反而以协同方式激活WEE1的翻译过程。本研究数据表明，RNA诱导沉默复合物与CPEB1介导的翻译调控在细胞周期调控中至关重要，且该调控过程具有协调性，可在细胞周期进程中从抑制状态切换为激活状态。