Mitotic spindle regulation and cell-cycle dependent proteolysis
Previous and current research
We have been investigating two aspects of cell cycle and growth control using fission yeast as a model system. One is the mechanism underlying bipolar spindle formation, and the other is the role for the SCF (Skp1-Cul1/Cdc53-F-box) ubiquitin ligase. The microtubule cytoskeleton displays various morphologies in a cell cycle and developmental stage-specific manner. Our research interest focuses on the formation of bipolar mitotic spindle. Any errors in forming this structure would lead to chromosome instability that results in production of aneuploid progenies, a hallmark of many cancerous cells. We have been characterising a series of conserved microtubule-binding proteins in fission yeast. These include the γ-tubulin complex, conserved microtubule-associated proteins and kinesin motors. It is noteworthy that these human homologues are intimately implicated in cellular transformation, as these genes/proteins are known to be overproduced or mis-regulated in many tumour cell lines.
Ubiquitin-dependent proteolysis is crucial for cell cycle progression and proliferation. SCF complexes recruit multiple substrates through individual F-box proteins, substrate-specific adaptor proteins, and are required for spatially and temporally regulated ubiquitylation (and degradation) of a magnitude of substrate proteins. Each organism contains the defined number of F-box proteins, e.g. ∼50 in human and ∼20 in yeast. We focus our analysis on roles for 16 F-box proteins encoded by the fission yeast genome and attempt to identify individual substrates.
Future projects
We would like to understand the molecular pathways leading to mitotic bipolar spindles. For this purpose, genome-wide approaches will be undertaken. Also we aim to identify a whole set of substrate proteins that are degraded via SCF and their roles in cell cycle and growth control. Our efforts will contribute significantly towards understanding of the molecular bases underlying tumorigenesis and help develop novel pharmaceutical drugs for cancer treatment.
