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Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells.


Cyclin E is an unstable protein that is degraded in a ubiquitin- and proteasome- dependent pathway. Two factors stimulate cyclin E ubiquitination in vivo: when it is free of its CDK partner, and when it is phosphorylated on threonine 380. We pursued the first of these pathways by using a two-hybrid screen to identify proteins that could bind only to free cyclin E. This resulted in the isolation of human Cul-3, a member of the cullin family of E3 ubiquitin-protein ligases. We found that Cul-3 was bound to cyclin E but not to cyclin E-Cdk2 complexes in mammalian cells, and that overexpression of Cul-3 increased ubiquitination of cyclin E but not other cyclins. Conversely, deletion of the Cul-3 gene in mice caused increased accumulation of cyclin E protein, and had cell-type-specific effects on S-phase regulation. In the extraembryonic ectoderm, in which cells undergo a standard mitotic cycle, there was a greatly increased number of cells in S phase. In the trophectoderm, in which cells go through endocycles, there was a block to entry into S phase. The SCF pathway, which targets cyclins for ubiquitination on the basis of their phosphorylation state, and the Cul-3 pathway, which selects cyclin E for ubiquitination on the basis of its assembly into CDK complexes, may be complementary ways to control cyclin abundance.

Pubmed ID: 10500095


  • Singer JD
  • Gurian-West M
  • Clurman B
  • Roberts JM


Genes & development

Publication Data

September 15, 1999

Associated Grants


Mesh Terms

  • 3T3 Cells
  • Animals
  • Blastocyst
  • Cell Cycle Proteins
  • Cloning, Molecular
  • Cullin Proteins
  • Cyclin E
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Genetic
  • Phenotype
  • Protein Binding
  • S Phase
  • Saccharomyces cerevisiae
  • Signal Transduction
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Ubiquitins