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

Publication Type:

Journal Article

Source:

Developmental cell, Volume 15, Issue 6, p.890-900 (2008)

Keywords:

2008, Amino Acid Motifs, Amino Acid Sequence, Animals, Basic Sciences Division, cell cycle, Center-Authored Paper, Cullin Proteins, Drosophila melanogaster, Drosophila Proteins, E2F1 Transcription Factor, Flow Cytometry Core Facility, Gene Expression Regulation, Genomics Core Facility, Models, Biological, PHOSPHORYLATION, Protein Binding, Retinoblastoma Protein, S Phase, Scientific Imaging Core Facility, Sequence Homology, Amino Acid, Shared Resources, Temperature

Abstract:

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.