Nurse Laboratory Current Research
In recent years, publications from the lab have developed understanding of the CDK system by reducing its complex and often mystifying regulation to a minimal control network that, despite its simplicity, preserves proper cell cycle control and also enables rigorous experimental investigation.
The multitude of cyclins and CDKs appearing periodically during the cell cycle suggested that specialized CDKs with qualitatively different substrate specificities might drive different cell cycle transitions. The laboratory has systematically investigated this qualitative model and demonstrated its inadequacy. In its place, a largely quantitative model as the core principle establishing cell cycle temporal order has been proposed. Through experiments using fission yeast, the laboratory has shown that a single CDK-cyclin is sufficient to establish the temporal order of both mitotic and meiotic cell cycles, that CDK activity rises continuously throughout the cell cycle, that different CDK substrates are phosphorylated at distinct activity thresholds, and critically, that G1/S and G2/M CDKs have nearly identical substrate specificities in vivo. These findings represent a paradigm shift in our understanding of cell cycle control, contradicting the prevailing qualitative model and establishing that a quantitative rheostat mechanism governs cell cycle progression.
The laboratory has also made key discoveries regarding the spatial regulation of cell growth and division. We identified and characterized genes required for normal cell polarity as well as spatial controls that prevent CDK activation at the cell periphery, thereby ensuring the nucleus divides centrally within the cell. More recently, it has been demonstrated that nuclear CDK activity serves as the cell cycle pacemaker, providing a sensitive link to DNA-related checkpoint controls. Only when activated in the nucleus is CDK exported to the cytoplasm, triggering mitosis throughout the cell.
The laboratory has revealed the fundamental importance of CKS (originally discovered by the lab in the 1980s as Suc1 in fission yeast), establishing it as a third universal component of the CDK-cyclin complex and a major general regulator of CDK activity. CKS enhances the phosphorylation of approximately 200 CDK substrates in vivo and controls access of the Wee1 and Cdc25 regulators to the CDK-cyclin complex, thereby modulating CDK activity through Y15 phosphorylation. This advance has been combined with comprehensive in vivo studies identifying over 400 CDK substrates, and the development of novel mass spectrometry assays to measure CDK activity in living cells.
