Regulation of Ubiquitin Mediated Proteolysis of G1 Cyclins and the CDK Inhibitor p27 by the Cullin Gene Family in Normal and Tumorigenic Human Breast Cells
Abstract
The periodicity of CDK activity provides the molecular basis for unidirectional cell cycle progression and is partly controlled by ubiquitin-mediated proteolysis of both cyclins and CDK inhibitors. Deregulated expression of G1 CDK inhibitors and G1 cyclins has been directly linked to breast cancer development. The mechanisms regulating the ubiquitination of these two protein families constitute essential components of G1 cell cycle control in mammalian cells. Polyubiquitination of proteins is known to be catalyzed by a cascade of enzymes: E1 (ubiquitin activating), E2 (ubiquitin conjugating), and E3 (ubiquitin ligating). Two issues critical to our understanding of the regulation of protein turnover are how E3 ligases target proteins for ubiquitination and how they themselves are regulated. We have found that cullins partner with another multigene family of evolutionarily conserved proteins, the ROC/APC11 family, to form a complex that contains E3 ubiquitin ligase activity. We have shown that one cullin/ROC enzyme is important for the G1/S transition due to its role in ubiquitinating a G1 CDK inhibitor. We have also been able to implicate another cullin/ROC E3 ligase in the proper progression of mitosis, demonstrating the importance of cullin/ROC ligases at two important cell cycle transitions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA389310
Entities
People
- Jennifer Michel
Organizations
- University of North Carolina at Chapel Hill