Liu Jun, Schmitz John C, Lin Xiukun, Tai Ningwen, Yan Wu, Farrell Michael, Bailly Michelle, Chen Tian min, Chu Edward
Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine, USA.
Biochim Biophys Acta. 2002 Jul 18;1587(2-3):174-82. doi: 10.1016/s0925-4439(02)00080-7.
Studies from our laboratory have shown that the folate-dependent enzyme, thymidylate synthase (TS), functions as an RNA binding protein. There is evidence that TS, in addition to interacting with its own TS mRNA, forms a ribonucleoprotein complex with a number of other cellular mRNAs, including those corresponding to the p53 tumor suppressor gene and the myc family of transcription factors. Using both in vitro and in vivo model systems, we have demonstrated that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of TS to the p53 mRNA, is translational repression. Herein, we review current work on the translational autoregulatory control of TS expression and discuss the molecular elements that are required for the TS protein-TS mRNA interaction. TS may play a critical role in regulating the cell cycle and the process of apoptosis through its regulatory effects on expression of p53 and perhaps other cell cycle related proteins. Finally, the ability of TS to function as a translational regulator may have important consequences with regard to the development of cellular resistance to various anticancer drugs.
我们实验室的研究表明，叶酸依赖性酶胸苷酸合成酶（TS）可作为一种RNA结合蛋白发挥作用。有证据表明，TS除了与其自身的TS mRNA相互作用外，还与许多其他细胞mRNA形成核糖核蛋白复合物，包括那些与p53肿瘤抑制基因和myc转录因子家族相对应的mRNA。通过使用体外和体内模型系统，我们已经证明TS蛋白与其自身同源mRNA结合以及TS与p53 mRNA结合的功能后果是翻译抑制。在此，我们综述了目前关于TS表达的翻译自调控控制的研究工作，并讨论了TS蛋白与TS mRNA相互作用所需的分子元件。TS可能通过对p53以及可能其他细胞周期相关蛋白表达的调节作用，在调节细胞周期和细胞凋亡过程中发挥关键作用。最后，TS作为翻译调节因子的能力可能对细胞对各种抗癌药物的耐药性发展产生重要影响。
