Regulation of Mitosis and Meiosis
Mitosis, centrosomes, kinetochores, Polo-like kinases, Aurora kinases
Late 19th century descriptions of mitosis are amazingly accurate. In “Zellsubstanz, Kern und Zelltheilung (1882)”, Walther Flemming showed enormous insight into cell division. Glimpses of molecular understanding came a century later, rewarded by a Nobel Prize to Lee Hartwell, Paul Nurse and Tim Hunt in 2001 for their discoveries of key cell cycle regulators. Hartwell had dissected cell cycle progression in budding yeast discovering cdc28, its Cyclin Dependent Kinase (Cdk) gene; Nurse showed its fission yeast counterpart had conserved functions in mitosis; and Hunt discovered the regulatory subunits, Cyclins. Cyclin B is required for Cdk1 to be active in mitosis and its destruction at anaphase turns Cdk1 off.
We study mitosis in Drosophila melanogaster because of advantages offered by this model. Its syncytial embryos, for example, undergo mitosis every 10 minutes, among the most rapid cycles in metazoans. Accordingly embryos have a maternal dowry of mitotic regulators whose genes can be identified by maternal effect mutants. Through such mutants we first identified aurora and polo, genes encoding protein kinases that regulate spatial aspects of mitosis. Polo is targeted to proteins previously phosphorylated by Cdk1 to mediate its functions at centrosomes, kinetochores and the central spindle that orchestrate cytokinesis. Enlargement of centrosomes on the mitotic spindle was first described by Theodor Boveri, a contemporary of Flemming. We now know that Polo kinase is required for this and that the related Polo-like kinase 4 drives the duplication cycle of the pairs of centrioles within the centrosome, events we have studied in fly and human cells
In “Zur Frage der Entsthung Maligner Tumoren” (1914) Boveri insightfully predicited the existence of oncogenes and tumour suppressors and noted multiple centrosomes in many tumour cells. We now know many tumours have elevated levels of Aurora and Polo kinases which have become targets for development of chemical inhibitors for therapeutic purposes.
3 key publications
Archambault, V., and Glover, D.M. (2009) Polo-like kinases: conservation and divergence in their functions and regulation Nature Rev. Mol. Cell Biol. 10:265-75
Rodrigues-Martins, A., Riparbelli, M., Callaini, G., Glover, D.M., and Bettencourt-Dias, M. (2007) Revisiting the Role of the Mother Centriole in Centriole Biogenesis Science 316: 1046-1-50
Bettencourt Dias, M., Giet, R., Sinka, R., Mazumdar, A., Lock, W.G., Balloux, F., Zafiropoulos, P.J., Yamaguchi, S., Winter, S., Carthew, R.W., Cooper, M., Frenz, L. and Glover, D.M. (2004) Genome-wide survey of protein kinases required for cell cycle progression. Nature.432: 980-7