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Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1

Wei Xie1, Peng Jiang, Lin Miao

  • 1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China Hefei, Anhui, 230027, China.

Nucleic Acids Research
|April 18, 2006
PubMed

Insights

The transcription factor E2F1 directly activates the Smac/DIABLO gene promoter, initiating p53-independent apoptosis. This mechanism involves E2F1 binding to specific sites, upregulating Smac/DIABLO, and enhancing mitochondrial apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • E2F1 promotes cell cycle progression and apoptosis.
  • E2F1-induced apoptosis is typically p53-dependent via ARF.
  • The mechanism of E2F1-induced p53-independent apoptosis is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of E2F1-induced p53-independent apoptosis.
  • To investigate the direct regulation of proapoptotic genes by E2F1.
  • To identify novel downstream targets of E2F1 in apoptosis.

Main Methods:

  • Analysis of E2F1 binding to the Smac/DIABLO promoter using E2F1-binding sites (BS2, BS3).
  • Conditional induction of E2F1 activity in H1299 ER-E2F1 cells.
  • Assessment of Smac/DIABLO mRNA and protein levels.
  • RNA interference to reduce Smac/DIABLO expression.
  • Measurement of mitochondria-mediated apoptosis.

Main Results:

  • E2F1 directly binds and activates the Smac/DIABLO promoter at BS2 and BS3 sites.
  • E2F1 specifically activates these sites, unlike E2F2 or E2F3.
  • E2F1 upregulates Smac/DIABLO expression, leading to enhanced mitochondria-mediated apoptosis.
  • Reducing Smac/DIABLO expression significantly diminishes E2F1-induced apoptosis.

Conclusions:

  • E2F1 directly regulates Smac/DIABLO, a key factor in mitochondrial apoptosis.
  • This represents a novel p53-independent pathway for E2F1-mediated apoptosis.
  • E2F1's role in apoptosis extends beyond p53-dependent pathways through direct regulation of mitochondrial factors.

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