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PMID:10500095
| Citation |
Singer, JD, Gurian-West, M, Clurman, B and Roberts, JM (1999) Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev. 13:2375-87 |
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| Abstract |
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. |
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| Keywords |
3T3 Cells; Animals; Blastocyst/cytology; Cell Cycle Proteins/genetics; Cell Cycle Proteins/physiology; Cloning, Molecular; Cullin Proteins; Cyclin E/metabolism; Embryo, Mammalian/anatomy & histology; Gene Expression Regulation, Developmental; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; Phenotype; Protein Binding; S Phase/physiology; Saccharomyces cerevisiae/metabolism; Signal Transduction; Tissue Distribution; Tumor Cells, Cultured; Ubiquitins/metabolism |
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Significance
Annotations
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