PMID- 25658582
OWN - NLM
STAT- MEDLINE
DCOM- 20150921
LR  - 20201217
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 11
IP  - 2
DP  - 2015 Feb
TI  - Cell cycle control by a minimal Cdk network.
PG  - e1004056
LID - 10.1371/journal.pcbi.1004056 [doi]
LID - e1004056
AB  - In present-day eukaryotes, the cell division cycle is controlled by a complex 
      network of interacting proteins, including members of the cyclin and 
      cyclin-dependent protein kinase (Cdk) families, and the Anaphase Promoting 
      Complex (APC). Successful progression through the cell cycle depends on precise, 
      temporally ordered regulation of the functions of these proteins. In light of 
      this complexity, it is surprising that in fission yeast, a minimal Cdk network 
      consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and 
      mitosis in a manner that is indistinguishable from wild type. To improve our 
      understanding of the cell cycle regulatory network, we built and analysed a 
      mathematical model of the molecular interactions controlling the G1/S and G2/M 
      transitions in these minimal cells. The model accounts for all observed 
      properties of yeast strains operating with the fusion protein. Importantly, 
      coupling the model's predictions with experimental analysis of alternative 
      minimal cells, we uncover an explanation for the unexpected fact that elimination 
      of inhibitory phosphorylation of Cdk is benign in these strains while it strongly 
      affects normal cells. Furthermore, in the strain without inhibitory 
      phosphorylation of the fusion protein, the distribution of cell size at division 
      is unusually broad, an observation that is accounted for by stochastic 
      simulations of the model. Our approach provides novel insights into the 
      organization and quantitative regulation of wild type cell cycle progression. In 
      particular, it leads us to propose a new mechanistic model for the phenomenon of 
      mitotic catastrophe, relying on a combination of unregulated, 
      multi-cyclin-dependent Cdk activities.
FAU - Gerard, Claude
AU  - Gerard C
AD  - Oxford Centre for Integrative Systems Biology, Department of Biochemistry, 
      University of Oxford, Oxford, United Kingdom.
FAU - Tyson, John J
AU  - Tyson JJ
AD  - Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United 
      States of America.
FAU - Coudreuse, Damien
AU  - Coudreuse D
AD  - Institut de Genetique et Developpement de Rennes, CNRS UMR 6290, Rennes, France.
FAU - Novak, Bela
AU  - Novak B
AD  - Oxford Centre for Integrative Systems Biology, Department of Biochemistry, 
      University of Oxford, Oxford, United Kingdom.
LA  - eng
GR  - R01 GM078989/GM/NIGMS NIH HHS/United States
GR  - 5R01-GM078989-07/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150206
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
MH  - Cell Cycle Checkpoints/*physiology
MH  - Computational Biology
MH  - Cyclin-Dependent Kinases/metabolism/*physiology
MH  - *Models, Biological
MH  - Phosphorylation/physiology
MH  - Schizosaccharomyces/metabolism/physiology
PMC - PMC4319789
COIS- The authors have declared that no competing interests exist.
EDAT- 2015/02/07 06:00
MHDA- 2015/09/22 06:00
PMCR- 2015/02/06
CRDT- 2015/02/07 06:00
PHST- 2014/08/29 00:00 [received]
PHST- 2014/11/21 00:00 [accepted]
PHST- 2015/02/07 06:00 [entrez]
PHST- 2015/02/07 06:00 [pubmed]
PHST- 2015/09/22 06:00 [medline]
PHST- 2015/02/06 00:00 [pmc-release]
AID - PCOMPBIOL-D-14-01582 [pii]
AID - 10.1371/journal.pcbi.1004056 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2015 Feb 6;11(2):e1004056. doi: 10.1371/journal.pcbi.1004056. 
      eCollection 2015 Feb.