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Deregulation of Rb-E2F1 axis causes chromosomal instability by engaging the transactivation function of

Somsubhra Nath1, Abhishek Chowdhury1, Sanjib Dey1

  • 1Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.

Molecular and Cellular Biology
|November 5, 2014
PubMed

Insights

E2F1 directly regulates UbcH10 gene expression, impacting cell cycle progression. This pathway, when deregulated by Rb inactivation, leads to chromosomal instability and aneuploidy in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Biology

Background:

  • E2F transcription factors regulate cell cycle genes, including roles in mitosis.
  • The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation.
  • Previous work identified Cdc20 as a UbcH10 regulator, but its DNA binding mechanism was unknown.

Purpose of the Study:

  • To investigate the role of E2F1 in regulating the UbcH10 gene.
  • To elucidate the mechanism of Cdc20 complex recruitment to the UBCH10 promoter.
  • To understand the consequences of E2F1-mediated UbcH10 regulation on mitotic progression and chromosomal stability.

Main Methods:

  • Chromatin immunoprecipitation assays to assess E2F1 binding to the UBCH10 promoter.
  • Reporter gene assays to measure UbcH10 promoter activity.
  • Cell cycle analysis and chromosomal abnormality scoring in response to E2F1 modulation and Rb inactivation.

Main Results:

  • E2F1-DP1 heterodimers bind to the UBCH10 promoter, mediating its transactivation.
  • Rb inactivation enhances E2F1-mediated UBCH10 transactivation.
  • E2F1-dependent UbcH10 regulation disrupts mitotic progression, causing premature anaphase, chromosomal abnormalities, and aneuploidy.

Conclusions:

  • E2F1, in complex with DP1, recruits the Cdc20-APC/C complex to the UBCH10 promoter.
  • Rb inactivation leads to excess E2F1, deregulating UbcH10 expression and promoting chromosomal instability in cancer cells.

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