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An alternative splicing network links cell-cycle control to apoptosis

Michael J Moore1, Qingqing Wang, Caleb J Kennedy

  • 1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

Cell
|August 14, 2010
PubMed

Insights

Alternative splicing regulates cell death and is disrupted in diseases. This study reveals a network linking cell-cycle control to apoptosis through alternative splicing of key genes.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Alternative splicing is a key mechanism for biological regulation and diversity.
  • Dysregulation of alternative splicing is implicated in various diseases, including cancer.
  • The Bcl2 family of apoptosis factors plays a critical role in programmed cell death.

Purpose of the Study:

  • To investigate the global control of alternative splicing in human cells.
  • To identify regulators of alternative splicing for Bcl-x and Mcl1 mRNA.
  • To understand the link between cell-cycle control and apoptosis via splicing.

Main Methods:

  • Genome-wide siRNA screen to identify splicing regulators.
  • Analysis of mRNA splicing patterns for Bcl2 family apoptosis factors.
  • Investigation of the role of cell-cycle factors and aurora kinase A.

Main Results:

  • A network of cell-cycle factors, including aurora kinase A, was identified as regulators of Bcl-x and Mcl1 splicing.
  • Mitotic arrest induced by drugs or siRNAs promoted proapoptotic splicing of Bcl-x, Mcl1, and caspase-9.
  • Posttranslational turnover of splicing regulator ASF/SF2 correlated with shifts in splice variants, impacting apoptosis.

Conclusions:

  • A novel alternative splicing network links cell-cycle control to apoptosis.
  • Coordinated upregulation of prodeath splice variants promotes apoptosis in cells undergoing mitotic arrest.
  • Splicing regulator ASF/SF2 plays a global role in regulating apoptosis through alternative splicing.

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