title: Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase.
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.
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Shusaku T
authors.initials: ST
authors.lastname: Shibutani
authors.forename: Aida Flor A
authors.initials: AF
authors.lastname: de la Cruz
authors.forename: Vuong
authors.initials: V
authors.lastname: Tran
authors.forename: William J
authors.initials: WJ
authors.lastname: Turbyfill
authors.forename: Tânia
authors.initials: T
authors.lastname: Reis
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Duronio
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D044842:Cullin Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D050687:E2F1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D017386:Sequence Homology, Amino Acid; D013696:Temperature
chemical_list: C524852:Cul4 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein