E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

Cell Death Differ. 2008 Dec;15(12):1815-23. doi: 10.1038/cdd.2008.135. Epub 2008 Sep 19.

Abstract

The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the Ser-Rich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cyclophosphamide / pharmacology
  • DNA Damage
  • E2F1 Transcription Factor / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Binding / drug effects
  • RNA Precursors / metabolism
  • Ribonucleoproteins / genetics*
  • Ribonucleoproteins / metabolism
  • Serine-Arginine Splicing Factors
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Nuclear Proteins
  • RNA Precursors
  • Ribonucleoproteins
  • bcl-X Protein
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • Cyclophosphamide
  • Caspase 8
  • Caspase 9