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The c-MYC-interacting proapoptotic tumor suppressor BIN1 is a transcriptional target for E2F1 in response to DNA

E K Cassimere1, S Pyndiah, D Sakamuro

  • 1Division of Cancer Biology, Department of Pathology, School of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Cell Death and Differentiation
|July 25, 2009
PubMed

Insights

The transcription factor E2F1 activates the tumor suppressor BIN1, initiating a unique cell death pathway in response to DNA damage. This finding offers new insights into cancer therapy mechanisms.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • The transcription factor E2F1 is known to initiate cell-cycle and mediate apoptosis following DNA damage.
  • Understanding E2F1 effector pathways is crucial for developing E2F1-induced apoptosis-based cancer therapies.

Purpose of the Study:

  • To investigate the role of the proapoptotic tumor suppressor BIN1 as a downstream effector of E2F1-mediated apoptosis.
  • To elucidate the mechanism by which E2F1 regulates BIN1 expression and its contribution to DNA damage-induced cell death.

Main Methods:

  • Analysis of the human BIN1 promoter activity in response to E2F1 expression.
  • Depletion of E2F1 using small interfering RNA (siRNA) and germline deletion.
  • Treatment with DNA-damaging agents like etoposide.
  • Chromatin immunoprecipitation (ChIP) assays to assess E2F1 binding to the BIN1 promoter.
  • Antisense (AS) oligonucleotide suppression of BIN1 expression.

Main Results:

  • Ectopic E2F1 activated the human BIN1 promoter, demonstrating transcriptional regulation.
  • E2F1 depletion or deletion resulted in reduced BIN1 levels.
  • DNA-damaging agents increased BIN1 levels in an E2F1-dependent manner.
  • E2F1 directly bound to the BIN1 gene promoter following etoposide treatment.
  • Suppression of BIN1 attenuated E2F1 and etoposide-induced cell death.

Conclusions:

  • BIN1 is a novel transcriptional target of E2F1.
  • E2F1-induced BIN1 expression mediates a unique form of apoptosis in response to DNA damage.
  • This pathway represents a distinct mechanism of cell death, independent of p53, p73, and caspases in this context.

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