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

E2F transcription factors are key regulators of cell proliferation that are inhibited by pRb family tumor suppressors. pRb-independent modes of E2F inhibition have also been described, but their contribution to animal development and tumor suppression is unclear. Here, we show that S phase-specific destruction of Drosophila E2f1 provides a novel mechanism for cell cycle regulation. E2f1 destruction is mediated by a PCNA-interacting-protein (PIP) motif in E2f1 and the Cul4(Cdt2) E3 ubiquitin ligase and requires the Dp dimerization partner but not direct Cdk phosphorylation or Rbf1 binding. E2f1 lacking a functional PIP motif accumulates inappropriately during S phase and is more potent than wild-type E2f1 at accelerating cell cycle progression and inducing apoptosis. Thus, S phase-coupled destruction is a key negative regulator of E2f1 activity. We propose that pRb-independent inhibition of E2F during S phase is an evolutionarily conserved feature of the metazoan cell cycle that is necessary for development.

Pubmed ID: 19081076


  • Shibutani ST
  • de la Cruz AF
  • Tran V
  • Turbyfill WJ
  • Reis T
  • Edgar BA
  • Duronio RJ


Developmental cell

Publication Data

December 16, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM057859
  • Agency: NIGMS NIH HHS, Id: R01 GM057859-08
  • Agency: NIGMS NIH HHS, Id: R01 GM057859-09
  • Agency: NIGMS NIH HHS, Id: R01 GM57859

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Cycle
  • Cullin Proteins
  • Drosophila Proteins
  • Drosophila melanogaster
  • E2F1 Transcription Factor
  • Gene Expression Regulation
  • Models, Biological
  • Phosphorylation
  • Protein Binding
  • Retinoblastoma Protein
  • S Phase
  • Sequence Homology, Amino Acid
  • Temperature