Intrinsic Negative Cell Cycle Regulation Provided by PIP Box- and Cul4Cdt2-Mediated Destruction of E2f1 during S Phase
- Resource Type
- Authors
- Robert J. Duronio; Aida Flor A. de la Cruz; Bruce A. Edgar; Vuong Tran; Tânia Reis; Shusaku Shibutani; William J. Turbyfill
- Source
- Developmental Cell. 15(6):890-900
- Subject
- DNA Replication
endocrine system
Amino Acid Motifs
DEVBIO
CELLCYCLE
Models, Biological
Retinoblastoma Protein
General Biochemistry, Genetics and Molecular Biology
Article
S Phase
03 medical and health sciences
0302 clinical medicine
Cyclin-dependent kinase
Proliferating Cell Nuclear Antigen
E2F1
Humans
Animals
Drosophila Proteins
Amino Acid Sequence
Phosphorylation
E2F
Molecular Biology
030304 developmental biology
0303 health sciences
Stem Cell Factor
biology
Sequence Homology, Amino Acid
Cell growth
Ubiquitin
Cell Cycle
Retinoblastoma protein
Temperature
Cell Biology
DNA
Cell cycle
Cullin Proteins
3. Good health
Ubiquitin ligase
Cell biology
Drosophila melanogaster
Gene Expression Regulation
030220 oncology & carcinogenesis
biology.protein
biological phenomena, cell phenomena, and immunity
E2F Transcription Factors
E2F1 Transcription Factor
Protein Binding
Developmental Biology
- Language
- ISSN
- 1534-5807
Summary 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.