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Cell Cycle Control Laboratory
Hiro Yamano, PhD - Group Leader
Margaret Hanwell, Bsc
Helene Labit, PhD
Michelle Trickey, PhD
We have moved!
With immediate effect the Cell Cycle Control Laboratory has moved to UCL Cancer
Institute, University College London.
Our new contact details are as follows:
UCL Cancer Institute
University College London
Paul O'Gorman Building
72 Huntley Street
London WC1E 6BT
Tel: +44(0)20-7679-6498
Fax: +44(0)20-7679-6817
Email: h.yamano@cancer.ucl.ac.uk
We are using a combination of biochemistry, genetics and cell biology to uncover the mechanisms how cell growth and cell cycle are regulated by the ubiquitin-mediated proteolysis.
Our bodies are composed of many millions of individual cells and each cell inherits genetic information through ordered cell cycle events including DNA replication and chromosome segregation. Since most of these events are regulated by proteins, selective and programmed protein degradation is vital.
The ubiquitin pathway is an ATP-dependent tagging system for protein degradation. It is an essential system in eukaryotic cells, where it is used for degrading damaged and misfolded proteins and also for degrading short-lived regulatory proteins during processes such as the cell cycle, transcription, signal transduction and development.
The anaphase-promoting complex/cyclosome (APC/C) is one of the major cellular ubiqutin ligases that ensures accurate cell cycle progression (i.e. cell growth) and faithful chromosome segregation to daughter cells. Aberrations in chromosome segregation can lead to aneuploidy and birth defects such as Down's syndrome, and could play a significant role in cancer progression.
Whilst most of subunits of the APC/C have been identified, very little is understood about their precise regulation and mechanisms of ubiquitylation. We have established a cell-free system based on Xenopus laevis egg extracts that recapitulates several aspects of the APC/C-dependent ubiquitylation and proteolysis. We seek to decipher the mechanisms by which the APC/C recognises substrates and ubiquitylates them, and to unravel how the APC/C activities are controlled by the regulatory networks such as checkpoints, kinases and phosphatases. In addition, to study the in vivo function and regulation of the APC/C, we use the fission yeast, Schizosaccharomyces pombe as a model organism, which is highly amenable to genetic, biochemical and genomic studies. These combined approaches will greatly improve our understanding of the molecular mechanisms how the ubiquitin system works to target and degrade their substrates.
Furthermore, our work will ultimately contribute to more effective strategies for developing drugs that will be useful in cancer prevention and the possible diagnosis and treatment of cancer and other diseases.
Selected references
Ors, A., Grimaldi, M., Kimata, Y., Wilkinson, C.R.M., Jones, N. and Yamano,
H. (2009) The transcription factor Atf1 binds and activates the APC/C
ubiquitin ligase in fission yeast. J. Biol. Chem., 284: 23989-23994.
Yamano, H., Trickey, M. Grimaldi, M. and Kimata, Y. (2009) In vitro assays
for the anaphase-promoting complex/cyclosome (APC/C) in Xenopus egg extracts.
Methods Mol. Biol., 545:287-300.
Fry, A.M. and Yamano, H. (2008) Under arrest in mitosis: Cdc20 dies twice.
Nat. Cell Biol., 10: 1385-1387.
Kimata, Y., Baxter, J.E., Fry, A.M. and Yamano, H. (2008) A role for the
Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from
substrate recruitment. Mol. Cell., 32: 576-583.
Trickey, M., Grimaldi, M. and Yamano, H. (2008)
The anaphase-promoting complex/cyclosome (APC/C) controls repair and
recombination by ubiquitylating Rhp54 in fission yeast.
Mol. Cell. Biol., 28: 3905-3916.
Kimata, Y., Trickey, M., Izawa, D., Gannon, J., Yamamoto, M. and Yamano, H.
(2008)
A mutual inhibition between APC/C and its substrate Mes1 required for
meiotic progression in fission yeast.
Dev. Cell, 14: 446-454.
Fry, A.M. and Yamano, H. (2006)
APC/C-mediated degradation in early mitosis: How to avoid spindle assembly
checkpoint inhibition
Cell Cycle, 5: 1487-1491.
Hayes, M.J., Kimata, Y., Wattam, S.L., Lindon, C., Mao, G. Yamano, H. and
Fry, A.M. (2006)
Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with
the APC/C.
Nature Cell Biol., 8: 607-614.
Kimata, Y. and Yamano, H. (2006)
Structural analysis sheds light on APC/C-mediated ubiquitylation.
Dev. Cell, 10: 4-5.
Turnell, A.S., Stewart, G.S., Grand, R.J.A., Rookes, S.M.,
Martin, A., Yamano, H., Elledge, S.J. and Gallimore, P.H. (2005)
The APC/C and CBP/p300 co-operate to regulate transcription and cell cycle
progression.
Nature, 438: 690-695.
Izawa, D., Goto, M., Yamashita, A., Yamano, H. and Yamamoto, M. (2005)
Fission yeast Mes1p ensures the onset of meiosis II by blocking degradation of
cyclin Cdc13p.
Nature, 434: 529-533.
Yamano, H., Kominami, K. I., Harrison, C., Kitamura, K., Katayama, S., Dhut,
S., Hunt, T. and Toda, T. (2004)
Requirement of the SCFPop1/Pop2 ubiquitin
ligase for degradation of the fission yeast S-phase cyclin Cig2.
J. Biol. Chem.
279: 18974-18980.
Yamano, H., Gannon, J., Mahbubani, H. and Hunt, T. (2004)
Cell
cycle-regulated recognition of the destruction box of cyclin B by the APC/C in
Xenopus egg extracts.
Mol. Cell, 13: 137-147.
Hames, R.S., Wattam, S.L., Yamano, H., Bacchieri, R. and Fry, A.M. (2001)
APC/C-mediated
destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends
upon a cyclin A-type D-box.
EMBO J., 20: 7117-7127.
Yamano, H., Kitamura, K., Kominami, K., Lehmann, A., Katayama, S., Hunt, T.
and Toda, T. (2000)
The spike of S phase cyclin Cig2 expression at the G1-S
border in fission yeast requires both APC and SCF ubiquitin ligases.
Mol. Cell,
6: 1377-1387.
Yamano, H., Tsurumi, C., Gannon, J. and Hunt, T. (1998)
The role of the
destruction box and its neighbouring lysine residues in cyclin B for anaphase
ubiquitin-dependent proteolysis in fission yeast: defining the D-box receptor.
EMBO J., 17: 5670-5678.
