Cell Cycle Control
Welcome to the cell cycle control research group
cyclinsCell cycle progression is regulated by cyclin dependent kinases (CDK). These kinase subunits exhibit low activity and need cyclin binding to become fully active. During the cell cycle different cyclins activate specific CDKs to regulate G1-phase progression, entry into S-phase and mitosis. The cell cycle phase specific expression of cyclins is regulated by several mechanisms, including cell cycle specific proteolysis. Cyclins, thus, contribute to the oscillating activity of these kinases and in addition contribute to substrate binding.
During mitosis cyclin A and the B-type cyclins become polyubiquitylated and subsequently degraded by the 26S proteasome. Cyclin degradation is essential as nondegradable mitotic cyclins prevent exit from mitosis. Cyclin degradation is controlled by the anaphase promoting complex/cyclosome (APC/C), a multisubunit ubiquitin ligase, which becomes activated by the WD40 repeat containing protein CDC20 in a CDK dependent. In addition to cyclins, the APC/C targets the separase inhibitor securin for proteolysis. Thus, the APC/C is required for separase-dependent sister chromatid separation and exit from mitosis.
To prevent precocious sister chromatid separation, the APC/C avtivity is controlled by the spindle assembly checkpoint, which monitors bipolar chromsome attachment to the mitotic spindle. As long as a single kinetochore remains unattached, the spindle assembly checkpoint prevents the degradation of securin and cyclin B1. Why cyclin A degradation is not prevented by the activity of the spindle assembly checkpoint is an unresolved question, whose solution might shed light in how the APC/C recognises its substrates.
Recent genetic analysis in mice has revealed the roles of cyclins and CDKs in proliferation and development. Whereas many of the cyclins and CDKs are required for development only cyclin A, cyclin B1 and Cdk1 appear to be essential for cellular proliferation. Whether cell cycle progression is primarily controlled by the substrate specificity of specific cyclin/CDK complexes or by substrate availability is a burning issue to understand cell cycle regulation.
Projects:
1. Mechanism of substrate specificty of CDK
2. Identification and analysis of mitotic CDK substrates
3. Mechanism of cyclin A degradation