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Dev Cell. 2008 Dec;15(6):890-900. doi: 10.1016/j.devcel.2008.10.003.

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

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

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.

Comment in

PMID:
19081076
[PubMed - indexed for MEDLINE]
PMCID:
PMC2644461
Free PMC Article

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