Cell Cycle in Development and Differentiation
Cell cycle, development, differentiation, ubiquitin, proteolysis, APC/C, centrosome, stem cell
The cell cycle is the process of reproduction of the cell, which involves duplication and partitioning of the genome DNA. In multicellular organisms such as humans, the cell cycle coordinates with development and differentiation in order to form and maintain the body and distinct organs. The precise execution of the cell cycle is fundamental to ensure the inheritance and health. Its dysregulation can cause fatal consequences such as cancer.
We are striving to understand the mechanisms responsible for cell cycle progression in the context of development in multicellular organisms. We are particularly interested in one of the principal cell cycle regulators, the anaphase-promoting complex or cyclosome (APC/C). The APC/C is an evolutionarily conserved ubiquitin ligase complex that drives cell cycle progression by controlling the levels of many proteins via the ubiquitin-dependent proteolysis in proliferating cells. However, it also plays important roles in quiescent and/or fully differentiated cells such as neurons, which suggests that its activity and functions are distinctively regulated through development. We explore such spatiotemporal regulatory systems in vivo using the fruit fly Drosophila melanogaster as a model system, combining in vitro approaches that include biochemical assays such as frog egg extracts and reconstituted ubiquitylation reactions.
We currently focus on the spatial regulation and specific functions of the APC/C at the centrosome, which is a complex organelle frequently implicated in cancer progression. The centrosome organises microtubules to form the mitotic apparatus and controls cell shapes and migration, thereby providing the cell with directional and spatial information important for developmental control. We investigate :
- the molecular basis of the physical link between the APC/C and the centrosome, and
- the roles of the APC/C in the cell cycle-dependent regulation and the developmental functions of the centrosome.
We further study the physical and structural natures of protein-protein interactions between the APC/C and its regulators or substrates, with the aim to develop compounds which target APC/C activity. This project is carried out by a collaboration with Dr. Alessio Ciulli in Department of Chemistry. Such APC/C targeting compounds may offer novel clinical therapeutics to combat the rapidly dividing cells prevalent in tumour.
- Kimata Y, Kitamura K, Fenner N, Yamano H. Mes1 controls the meiosis I to meiosis II transition by distinctly regulating the anaphase-promoting complex/cyclosome coactivators Fzr1/Mfr1 and Slp1 in fission yeast. Mol Biol Cell. 2011 May; 22(9):1486-9
- Kimata Y, Baxter JE, Fry AM, Yamano H. A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment. Mol Cell. 2008 Nov 21; 32(4):576-83
- Kimata Y, Trickey M, Izawa D, Gannon J, Yamamoto M, Yamano H. A mutual inhibition between APC/C and its substrate Mes1 required for meiotic progression in fission yeast. Dev Cell. 2008 Mar; 14(3):446-54
- Hayes MJ, Kimata Y (equally contributed), Wattam SL, Lindon C, Mao G, Yamano H, Fry AM. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nat Cell Biol. 2006 Jun; 8(6):607-14