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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Jab1/CSN5 mediates E2F dependent expression of mitotic and apoptotic but not DNA replication targets

Huarui Lu1, Xudong Liang, Olga A Issaenko

  • 1Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Cell Cycle (Georgetown, Tex.)
|September 23, 2011
PubMed

Insights

The study reveals that Jab1/CSN5 is crucial for expressing E2F target genes involved in apoptosis and mitosis, but not DNA replication. PI3K signaling interferes with Jab1/CSN5 and E2F1 complex formation, impacting gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Biology

Background:

  • E2F transcription factors regulate cell cycle and fate, controlling genes for DNA replication, mitosis, and apoptosis.
  • The E2F1 binding partner Jab1/CSN5 promotes E2F1-dependent apoptosis induction.
  • Mechanisms by which E2Fs coordinate diverse target gene expression remain unclear.

Purpose of the Study:

  • To elucidate how Jab1/CSN5 regulates E2F1-dependent transcription of target genes.
  • To identify E2F target genes differentially affected by Jab1/CSN5 depletion.
  • To investigate the interplay between PI3K signaling, Jab1/CSN5, and E2F1 in gene regulation and cancer.

Main Methods:

  • Gene expression analysis using shRNA to deplete Jab1/CSN5.
  • Chromatin immunoprecipitation (ChIP) to assess Jab1 and E2F1 co-occupancy of target genes.
  • Co-immunoprecipitation and PI3K activity assays to study protein complex formation and signaling.

Main Results:

  • Jab1/CSN5 depletion significantly reduced expression of apoptotic and mitotic E2F target genes, while DNA replication genes remained largely unaffected.
  • Jab1 and E2F1 co-occupied promoters of apoptotic and mitotic genes, but not replication genes.
  • Activated PI3K inhibited E2F1/Jab1 co-induction of apoptotic genes and disrupted E2F1/Jab1 complex formation.
  • Elevated Jab1/CSN5 levels strongly correlated with PI3K activity across multiple human cancers (breast, ovarian, lung, prostate).

Conclusions:

  • Jab1/CSN5 is essential for the expression of specific E2F target genes involved in apoptosis and mitosis.
  • PI3K signaling negatively regulates E2F1/Jab1 complex formation and function, impacting apoptosis-related gene expression.
  • The correlation between Jab1/CSN5 and PI3K activity in tumors suggests a potential regulatory axis in cancer progression.

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