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Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S

Shusaku T Shibutani1, Aida Flor A de la Cruz, Vuong Tran

  • 1Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.

Developmental Cell
|December 17, 2008
PubMed

Insights

Cell cycle regulation involves E2F transcription factors. This study reveals S phase-specific destruction of E2f1 as a novel inhibitory mechanism, crucial for animal development and tumor suppression.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Developmental Biology

Background:

  • E2F transcription factors regulate cell proliferation and are inhibited by pRb tumor suppressors.
  • pRb-independent E2F inhibition mechanisms are known but their developmental roles are unclear.

Purpose of the Study:

  • To investigate novel mechanisms of E2F regulation beyond pRb inhibition.
  • To elucidate the role of S phase-specific E2f1 destruction in cell cycle control and animal development.

Main Methods:

  • Utilized Drosophila melanogaster as a model organism.
  • Investigated the role of a PCNA-interacting-protein (PIP) motif in E2f1 destruction.
  • Examined the involvement of the Cul4(Cdt2) E3 ubiquitin ligase complex.

Main Results:

  • Demonstrated S phase-specific destruction of E2f1 mediated by its PIP motif and Cul4(Cdt2).
  • Showed that E2f1 lacking a functional PIP motif accumulates during S phase, enhancing cell cycle progression and apoptosis.
  • Confirmed that Dp dimerization is required, but Cdk phosphorylation and Rbf1 binding are not essential for this destruction pathway.

Conclusions:

  • S phase-coupled destruction of E2f1 is a critical negative regulator of its activity.
  • This pRb-independent inhibition of E2F during S phase is an evolutionarily conserved mechanism essential for metazoan development.

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