Boon-Unge Kritsanapol, Yu Qingming, Zou Tie, Zhou An, Govitrapong Piyarat, Zhou Jianhua
Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Chem Biol. 2007 Dec;14(12):1386-92. doi: 10.1016/j.chembiol.2007.11.004.
Exon 2 of the Bcl-x gene undergoes alternative splicing in which the Bcl-xS splice variant promotes apoptosis in contrast to the anti-apoptotic splice variant Bcl-xL. In this study, the regulation of the alternative splicing of pre-mRNA of Bcl-x was examined in response to emetine. Treatment of different types of cancer cells with emetine dihydrochloride downregulated the level of Bcl-xL mRNA with a concomitant increase in the mRNA level of Bcl-xS in a dose- and time-dependent manner. Pretreatment with calyculin A, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), blocked emetine-induced alternative splicing in contrast to okadaic acid, a specific inhibitor of PP2A in cells, demonstrating a PP1-mediated mechanism. Our finding on the regulation of RNA splicing of members of the Bcl-2 family in response to emetine presents a potential target for cancer treatment.
Bcl-x基因的外显子2发生可变剪接，其中Bcl-xS剪接变体促进细胞凋亡，这与抗凋亡剪接变体Bcl-xL相反。在本研究中，研究了Bcl-x前体mRNA可变剪接在应对依米丁时的调控情况。用盐酸依米丁处理不同类型的癌细胞，以剂量和时间依赖性方式下调Bcl-xL mRNA水平，同时伴随Bcl-xS mRNA水平的增加。用花萼海绵诱癌素A（一种蛋白磷酸酶1（PP1）和蛋白磷酸酶二磷酸酶2A（PP2A）的抑制剂）预处理，与冈田酸（一种细胞中PP2A的特异性抑制剂）相反，可阻断依米丁诱导的可变剪接，证明了一种PP1介导的机制。我们关于Bcl-2家族成员RNA剪接在应对依米丁时的调控的发现为癌症治疗提供了一个潜在靶点。
