Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2010 Aug 20;142(4):625-36. doi: 10.1016/j.cell.2010.07.019. Epub 2010 Aug 12.
Alternative splicing is a vast source of biological regulation and diversity that is misregulated in cancer and other diseases. To investigate global control of alternative splicing in human cells, we analyzed splicing of mRNAs encoding Bcl2 family apoptosis factors in a genome-wide siRNA screen. The screen identified many regulators of Bcl-x and Mcl1 splicing, notably an extensive network of cell-cycle factors linked to aurora kinase A. Drugs or siRNAs that induce mitotic arrest promote proapoptotic splicing of Bcl-x, Mcl1, and caspase-9 and alter splicing of other apoptotic transcripts. This response precedes mitotic arrest, indicating coordinated upregulation of prodeath splice variants that promotes apoptosis in arrested cells. These shifts correspond to posttranslational turnover of splicing regulator ASF/SF2, which directly binds and regulates these target mRNAs and globally regulates apoptosis. Broadly, our results reveal an alternative splicing network linking cell-cycle control to apoptosis.
可变剪接是生物调控和多样性的一个巨大来源，但在癌症和其他疾病中却失调了。为了研究人类细胞中可变剪接的全局调控，我们在全基因组 siRNA 筛选中分析了编码 Bcl2 家族凋亡因子的 mRNA 的剪接。该筛选鉴定了许多 Bcl-x 和 Mcl1 剪接的调节剂，特别是与极光激酶 A 相关的广泛的细胞周期因子网络。诱导有丝分裂阻滞的药物或 siRNA 促进 Bcl-x、Mcl1 和 caspase-9 的促凋亡剪接，并改变其他凋亡转录物的剪接。这种反应先于有丝分裂阻滞，表明促死亡剪接变体的协调上调促进了阻滞细胞的凋亡。这些变化与剪接调节因子 ASF/SF2 的翻译后周转相对应，ASF/SF2 直接结合并调节这些靶 mRNA，并全局调节细胞凋亡。广义而言，我们的结果揭示了一个将细胞周期控制与细胞凋亡联系起来的可变剪接网络。
