Group Leader:
Iain Hagan
After completing my PhD studies I went to Japan on a 4-year postdoctoral fellowship with Professor Mitsuhiro Yanagida in Kyoto University. I returned to the UK in 1993 with a Cancer Research Campaign Return Fellowship to establish a group in The University of Manchester. I continued to work in what later became the Faculty of Life Sciences at The University of Manchester, with further Cancer Research Campaign Fellowship support before moving to the Paterson Institute for Cancer Research in 2001. In 1999 I was awarded the Human Frontier Science Program 10th Anniversary Medal and in 2001 was the recipient of the BSCB Hooke Medal. I am currently a Senior Group Leader at the Paterson Institute for Cancer Research.
Postdoctoral Fellows
Marisa Alonso Nuñez
Marisa Madrid
Associate Scientist
Agnes Grallert
Graduate Students
Dorota Feret
Avinash Patel
Elvan Boke
Yisu Wang
Cell Division Group - Cut12 anchors polo kinase to the SPB
One of the models that we came up with to account for the suppression of cdc25.22 by stf1 mutants (we refer from here on to them as cut12.s alleles; cut12.s11 being stf1.1) was that they may prematurely activate the feedback loop to suppress Wee1 and so enable life without Cdc25. As the work in Xenopus had suggested that polo kinase was involved in this loop (Kumagai and Dunphy, 1996) we compared the localisation of fission yeast polo kinase, Plo1 in wild type cells with that cut12.s11 mutants. In wild type cells the protein showed a strong affinity for the SPB of mitotic but not interphase cells (Bahler et al., 1998; Mulvihill et al., 1999). In cut12.s11 cells however the protein associated with SPB at all stages of the cell cycle (Mulvihill et al., 1999).
Two hybrid and co-immunoprecipitation experiments showed that Cut12 bound to Plo1 (MacIver et al., 2003). Furthermore, we found that the activation of Plo1 kinase activity that normally accompanies commitment to mitosis was not seen in cut12.1 mutants and that both the mitotic and interphase Plo1 activities were increased by the cut12.s11 mutation (MacIver et al., 2003). Thus loss of Cut12 function blocks Plo1 activation and gain of Cut12 function boosts Plo1 activity and promotes premature association with the SPB. All of these data would be consistent with the model whereby cut12.s11 suppresses cdc25.22 mutation because it promotes Plo1 activity independently of commitment to mitosis.
This model predicts that the ability of cut12.s11 to suppress cdc25.22 should depend upon the functionality of Plo1. We therefore introduced two different conditional plo1 mutations into cut12.s11 cdc25.22 cells and asked whether cut12.s11 could still suppress cdc25.22 when Plo1 function was compromised. It could not. Further support for the model came with the finding that the induction of plo1 gene which had been mutated to introduce two mutations that dominantly activate the kinase, suppressed the growth defect of cdc25.22 (MacIver et al., 2003). We therefore are working with the model shown here that the association of Plo1 with the SPB is a critical step in regulating commitment to mitosis. The association between Cut12 and Plo1 is regulated at some level by a second mitotic protein kinase the NIMA related kinase Fin1. We think that it is highly likely that Plo1 associates with further components of the SPB. Genome interaction screens and functional assays of mitotic exit in budding yeast link the budding yeast polo kinase to the SPB associated proteins Spc72 and Bfa1 (Hu et al., 2001).
references
Bahler, J., Steever, A. B., Wheatley, S., Wang, Y. L., Pringle, J. R., Gould, K. L., and McCollum, D. (1998). Role of polo kinase and Mid1p in determining the site of cell division in fission yeast. Journal of Cell Biology 143, 1603-1616.
Hu, F., Wang, Y., Liu, D., Li, Y., Qin, J., and Elledge, S. J. (2001). Regulation of the Bub2/Bfa1 GAP complex by Cdc5 and cell cycle checkpoints. Cell 107, 655-665.
Kumagai, A., and Dunphy, W. G. (1996). Purification and molecular-cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science 273, 1377-1380.
MacIver, F. H., Tanaka, K., A.M., R., and Hagan, I. M. (2003). Physical and functional interactions between polo kinase and the spindle pole component Cut12 regulate mitotic commitment in S. pombe. Genes and Development 17, 1507-1523.
Mulvihill, D. P., Petersen, J., Ohkura, H., Glover, D. M., and Hagan, I. M. (1999). Plo1 kinase recruitment to the spindle pole body and its role in cell division in Schizosaccharomyces pombe. Mol Biol Cell 10, 2771-2785.