Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Oncogene. 2014 Jan 2;33(1):55-64. doi: 10.1038/onc.2012.548. Epub 2012 Nov 26.
The regulation of mRNA deadenylation constitutes a pivotal mechanism of the post-transcriptional control of gene expression. Here we show that the antiproliferative protein Tob, a component of the Caf1-Ccr4 deadenylase complex, is involved in regulating the expression of the proto-oncogene c-myc. The c-myc mRNA contains cis elements (CPEs) in its 3'-untranslated region (3'-UTR), which are recognized by the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB recruits Caf1 deadenylase through interaction with Tob to form a ternary complex, CPEB-Tob-Caf1, and negatively regulates the expression of c-myc by accelerating the deadenylation and decay of its mRNA. In quiescent cells, c-myc mRNA is destabilized by the trans-acting complex (CPEB-Tob-Caf1), while in cells stimulated by the serum, both Tob and Caf1 are released from CPEB, and c-Myc expression is induced early after stimulation by the stabilization of its mRNA as an 'immediate-early gene'. Collectively, these results indicate that Tob is a key factor in the regulation of c-myc gene expression, which is essential for cell growth. Thus, Tob appears to function in the control of cell growth at least, in part, by regulating the expression of c-myc.
mRNA 去腺苷酸化的调节构成了基因表达转录后控制的关键机制。在这里，我们表明，增殖抑制蛋白 Tob，是 Caf1-Ccr4 去腺苷酸酶复合物的一个组成部分，参与调节原癌基因 c-myc 的表达。c-myc mRNA 在其 3'非翻译区（3'UTR）中含有顺式元件（CPEs），这些元件被细胞质多聚腺苷酸化元件结合蛋白（CPEB）识别。CPEB 通过与 Tob 相互作用招募 Caf1 去腺苷酸酶，形成三元复合物 CPEB-Tob-Caf1，并通过加速其 mRNA 的去腺苷酸化和降解来负调控 c-myc 的表达。在静止细胞中，c-myc mRNA 被反式作用复合物（CPEB-Tob-Caf1）所稳定，而在受血清刺激的细胞中，Tob 和 Caf1 都从 CPEB 中释放出来，c-Myc 表达在刺激后早期通过其 mRNA 的稳定作为“即时早期基因”被诱导。总之，这些结果表明 Tob 是调节 c-myc 基因表达的关键因素，这对于细胞生长是必不可少的。因此，Tob 似乎至少在一定程度上通过调节 c-myc 的表达来控制细胞生长。
