Liao Baisong, Hu Yan, Brewer Gary
Department of Molecular Genetics, Microbiology, and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
Nat Struct Mol Biol. 2007 Jun;14(6):511-8. doi: 10.1038/nsmb1249. Epub 2007 May 7.
(A+U)-rich elements (AREs) within 3' untranslated regions are signals for rapid degradation of messenger RNAs encoding many oncoproteins and cytokines. The ARE-binding protein AUF1 contributes to their degradation. We identified MYC proto-oncogene mRNA as a cellular AUF1 target. Levels of MYC translation and cell proliferation were proportional to AUF1 abundance but inversely proportional to the abundance of the ARE-binding protein TIAR, a MYC translational suppressor. Both AUF1 and TIAR affected MYC translation via the ARE without affecting mRNA abundance. Altering association of one ARE-binding protein with MYC mRNA in vivo reciprocally affected mRNA association with the other protein. Finally, genetic experiments revealed that AUF1 and TIAR control proliferation by a MYC-dependent pathway. Together, these observations suggest a novel regulatory mechanism where tuning the ratios of AUF1 and TIAR bound to MYC mRNA permits dynamic control of MYC translation and cell proliferation.
3'非翻译区内富含（A+U）的元件（AREs）是许多癌蛋白和细胞因子编码信使核糖核酸快速降解的信号。ARE结合蛋白AUF1促成其降解。我们将MYC原癌基因信使核糖核酸鉴定为细胞内AUF1的作用靶点。MYC的翻译水平和细胞增殖与AUF1丰度成正比，但与ARE结合蛋白TIAR（一种MYC翻译抑制因子）的丰度成反比。AUF1和TIAR均通过ARE影响MYC翻译，而不影响信使核糖核酸丰度。改变一种ARE结合蛋白在体内与MYC信使核糖核酸的结合会相互影响信使核糖核酸与另一种蛋白的结合。最后，遗传学实验表明，AUF1和TIAR通过依赖MYC的途径控制细胞增殖。总之，这些观察结果提示了一种新的调控机制，即调节与MYC信使核糖核酸结合的AUF1和TIAR的比例可实现对MYC翻译和细胞增殖的动态控制。
