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A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis

Bing Wang1, Kang Liu, Fang-Tsyr Lin

  • 1Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Alabama 35294-3300, USA.

The Journal of Biological Chemistry
|October 21, 2004
PubMed

Insights

14-3-3 tau stabilizes E2F1 protein during DNA damage, inhibiting its ubiquitination and promoting apoptosis. This protein is crucial for E2F1-mediated apoptosis and the expression of apoptotic target genes.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Biochemistry

Background:

  • Genotoxic stress induces apoptosis via multiple signaling pathways.
  • E2F1 accumulation and function in apoptosis upon DNA damage are increasingly recognized.
  • ATM (ataxia-telangiectasia mutated) kinase mediates E2F1 phosphorylation during DNA damage, but the stabilization mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which ATM-mediated phosphorylation leads to E2F1 stabilization.
  • To investigate the role of 14-3-3 tau in regulating E2F1 stability and apoptosis during DNA damage.

Main Methods:

  • Investigated protein-protein interactions using co-immunoprecipitation.
  • Assessed protein ubiquitination levels.
  • Utilized siRNA to deplete 14-3-3 tau and E2F1, E2F2, E2F3.
  • Measured adriamycin-induced apoptosis.
  • Analyzed the expression of E2F1 apoptotic targets (p73, Apaf-1, caspases).

Main Results:

  • 14-3-3 tau directly interacts with ATM-phosphorylated E2F1.
  • 14-3-3 tau binding inhibits E2F1 ubiquitination, leading to E2F1 stabilization.
  • Depletion of 14-3-3 tau or E2F1, but not E2F2 or E2F3, abrogates adriamycin-induced apoptosis.
  • 14-3-3 tau is essential for the induction of E2F1-regulated apoptotic genes.

Conclusions:

  • 14-3-3 tau acts as a novel regulator of E2F1 protein stability.
  • 14-3-3 tau mediates E2F1 stabilization by inhibiting ubiquitination, thereby promoting apoptosis during DNA damage.
  • These findings reveal a critical role for 14-3-3 tau in the DNA damage response pathway involving E2F1.

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