Previous Seminars
ICaMB Seminar - Dr Yuu Kimata
- Venue: Baddiley Clark Seminar Room
- Start: Tue, 27 Jun 2017 13:00:00 BST
- End: Tue, 27 Jun 2017 14:00:00 BST
Coupling cell cycle to development – Novel roles of the APC/C in the coordination between cell proliferation and differentiation
The metazoan cell cycle must be tightly coordinated with differentiation, migration, tissue growth and morphogenesis to ensure development and homeostasis of the organism. Loss of this coordination underlies various human pathologies such as cancer, degenerative disorders and ageing. Despite such significance, the mechanisms underpinning the coordination remain largely elusive.
The anaphase-promoting complex or cyclosome (APC/C) is a multi-subunit ubiquitin ligase that regulates cell cycle progression via ubiquitin-dependent proteolysis, whose role beyond cell cycle control has been highlighted by its function in post-mitotic neurons. We have explored novel developmental roles of the APC/C by exploiting the fruit fly Drosophila melanogaster as an in vivo model. Through a proteomics approach, we have discovered an unanticipated physical and functional link between the APC/C and the major microtubule-organising centre, the centrosome. By recruiting the APC/C activator Fzr/CDH1, the centrosome facilitates destruction of an centrosomal substrate Aurora A (Meghini, et al., 2016). We also show that APC/CFzr contributes to the homeostasis of neural stem cells through destruction of a conserved centrosomal component Spd2.
Furthermore, by performing an in vivo RNAi screen targeting individual APC/C components, we have uncovered a novel function of the APC/C in directly modulating a major signalling pathway, the Wnt (Wingless in Drosophila) pathway, to regulate photoreceptor differentiation in the developing eye. Remarkably, this Wnt regulation is mediated by the G1-specific degradation of Nek2 kinase, a positive Wnt modulator and a known regulator of centrosome integrity (Martins et al., 2017).
Our findings have established the role of the master cell cycle regulator APC/C in coupling the cell cycle to differentiation through centrosomal events, pointing to the critical role for the activities of conserved cell cycle regulators in the coordination between cell proliferation and developmental processes.
Biography
2001-2004: PhD under Mitsuhiro Yanagida at Kyoto University in Japan. The regulatory mechanism of the APC/C in fission yeast.
2004-2009: Postdoc in Hiro Yamano’s lab at Marie Curie Research Institute in Surrey in UK. Substrate recognition mechanism of the APC/C and APC/C activation mechanism by APC/C activators using various in vitro assays and Xenopus egg cell cycle extracts, and the regulation of APC/C in fission yeast meiosis.
2009-2011: Postdoc in David Glover’s lab at University of Cambridge. The Developmental role of the APC/C in Drosophila.
2011-present: Group leader at Department of Genetics, University of Cambridge. CRUK Career Development Fellowship to investigate the role of the APC/C in centrosome regulation and development.