Abstract
Cytokinesis in fission yeast is controlled by a signal transduction pathway called the Septation Initiation Network (SIN). From a dynamical point of view the most interesting questions about the regulation of fission yeast cytokinesis are: how do wild type cells ensure that septation is initiated only once per cycle? Why does the control system stay in a continuously septating state in some mutant strains? And how is it that the SIN remains active when cytokinesis fails? To answer these questions we construct a simplified mathematical model of the SIN and graft this regulatory module onto our previous model of cyclin-dependent kinase (Cdk) dynamics in fission yeast cells. The SIN is both activated and inhibited by mitotic Cdk/cyclin complexes. As a consequence of this dual regulation, the SIN gets activated only once at the end of mitosis, when Cdk activity drops. The mathematical model describes the timing of septation not only in wild type cells but also in mutants where components of the SIN are knocked out. The model predicts phenotypes of some uncharacterized mutant cells and shows how a cytokinesis checkpoint can stop the cell cycle if septation fails.
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Abbreviations
- SIN:
-
Septation initiation network
- SPF:
-
S-phase promoting factor
- MPF:
-
M-phase promoting factor
- CDK:
-
Cyclin dependent kinase
- SPB:
-
Spindle pole body
- GEF:
-
Guanine nucleotide exchange factor
- GAP:
-
GTPase activating protein
References
Bahler J et al (1998) Role of polo kinase and Mid1p in determining the site of cell division in fission yeast. J Cell Biol 143:1603–1616
Balasubramanian MK, McCollum D, Surana U (2000) Tying the knot: linking cytokinesis to the nuclear cycle. J Cell Sci 113(Pt 9):1503–1513
Cerutti L, Simanis V (1999) Asymmetry of the spindle pole bodies and spg1p GAP segregation during mitosis in fission yeast. J Cell Sci 112(Pt 14):2313–2321
Chen KC, Csikasz-Nagy A, Gyorffy B, Val J, Novak B, Tyson JJ (2000) Kinetic analysis of a molecular model of the budding yeast cell cycle. Mol Biol Cell 11:369–391
Chen KC, Calzone L, Csikasz-Nagy A, Cross FR, Novak B, Tyson JJ (2004) Integrative analysis of cell cycle control in budding yeast. Mol Biol Cell 15:3841–3862
Ciliberto A, Novak B, Tyson JJ (2003) Mathematical model of the morphogenesis checkpoint in budding yeast. J Cell Biol 163:1243–1254
Creanor J, Mitchison JM (1994) The kinetics of H1 histone kinase activation during the cell cycle of wild-type and wee mutants of the fission yeast Schizosaccharomyces pombe. J Cell Sci 107:1197–1204
Cueille N et al (2001) Flp1, a fission yeast orthologue of the s. cerevisiae CDC14 gene, is not required for cyclin degradation or rum1p stabilisation at the end of mitosis. J Cell Sci 114:2649–2664
Esteban V, Blanco M, Cueille N, Simanis V, Moreno S, Bueno A (2004) A role for the Cdc14-family phosphatase Flp1p at the end of the cell cycle in controlling the rapid degradation of the mitotic inducer Cdc25p in fission yeast. J Cell Sci 117:2461–2468
Fankhauser C, Simanis V (1994) The cdc7 protein kinase is a dosage dependent regulator of septum formation in fission yeast. EMBO J 13:3011–3019
Fankhauser C, Marks J, Reymond A, Simanis V (1993) The S. pombe cdc16 gene is required both for maintenance of p34cdc2 kinase activity and regulation of septum formation: a link between mitosis and cytokinesis? EMBO J 12:2697–2704
Fournier N, Cerutti L, Beltraminelli N, Salimova E, Simanis V (2001) Bypass of the requirement for cdc16p GAP function in Schizosaccharomyces pombe by mutation of the septation initiation network genes. Arch Microbiol 175:62–69
Furge KA, Cheng QC, Jwa M, Shin S, Song K, Albright CF (1999) Regions of Byr4, a regulator of septation in fission yeast, that bind Spg1 or Cdc16 and form a two-component GTPase-activating protein with Cdc16. J Biol Chem 274:11339–11343
Goldbeter A, Koshland DEJ (1981) An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci USA 78:6840–6844
Gould KL, Simanis V (1997) The control of septum formation in fission yeast. Genes Dev 11:2939–2951
Grallert A, Krapp A, Bagley S, Simanis V, Hagan IM (2004) Recruitment of NIMA kinase shows that maturation of the S. pombe spindle-pole body occurs over consecutive cell cycles and reveals a role for NIMA in modulating SIN activity. Genes Dev 18:1007–1021
Guertin DA, Chang L, Irshad F, Gould KL, McCollum D (2000) The role of the sid1p kinase and cdc14p in regulating the onset of cytokinesis in fission yeast. EMBO J 19:1803–1815
Guertin DA, Trautmann S, McCollum D (2002a) Cytokinesis in eukaryotes. Microbiol Mol Biol Rev 66:155–178
Guertin DA, Venkatram S, Gould KL, McCollum D (2002b) Dma1 prevents mitotic exit and cytokinesis by inhibiting the septation initiation network (SIN). Dev Cell 3:779–790
Hirano T, Funahashi S, Uemura T, Yanagida M (1986) Isolation and characterization of schizosaccharomyces-pombe cut mutants that block nuclear division but not cytokinesis. EMBO J 5:2973–2979
Jaspersen SL, Morgan DO (2000) Cdc14 activates cdc15 to promote mitotic exit in budding yeast. Curr Biol 10:615–618
Karagiannis J, Bimbo A, Rajagopalan S, Liu J, Balasubramanian MK (2005) The nuclear kinase lsk1p positively regulates the septation initiation network and promotes the successful completion of cytokinesis in response to perturbation of the actomyosin ring in schizosaccharomyces pombe. Mol Biol Cell 16:358–371
Krapp A, Schmidt S, Cano E, Simanis V (2001) S. pombe cdc11p, together with sid4p, provides an anchor for septation initiation network proteins on the spindle pole body. Curr Biol 11:1559–1568
Krapp A, Gulli MP, Simanis V (2004) SIN and the art of splitting the fission yeast cell. Curr Biol 14:R722–R730
Le Goff X, Utzig S, Simanis V (1999a) Controlling septation in fission yeast: finding the middle, and timing it right. Curr Genet 35:571–584
Le Goff X, Woollard A, Simanis V (1999b) Analysis of the cps1 gene provides evidence for a septation checkpoint in Schizosaccharomyces pombe. Mol Gen Genet 262:163–172
Levchenko A, Iglesias PA (2002) Models of eukaryotic gradient sensing: application to chemotaxis of amoebae and neutrophils. Biophys J 82:50–63
Liu J, Wang H, Balasubramanian MK (2000) A checkpoint that monitors cytokinesis in Schizosaccharomyces pombe. J Cell Sci 113(Pt 7):1223–1230
Mehta S, Gould KL (2006) Identification of functional domains within the SIN kinase Cdc7. J Biol Chem:M600160200
Minet M, Nurse P, Thuriaux P, Mitchison JM (1979) Uncontrolled septation in a cell division cycle mutant of the fission yeast Schizosaccharomyces pombe. J Bacteriol 137:440–446
Mishra M, Karagiannis J, Trautmann S, Wang HY, McCollum D, Balasubramanian MK (2004) The Clp1p/Flp1p phosphatase ensures completion of cytokinesis in response to minor perturbation of the cell division machinery in Schizosaccharomyces pombe. J Cell Sci 117:3897–3910
Mondesert O, McGowan C, Russell P (1996) Cig2, a B-type cyclin, promotes the onset of S in Schizosaccharomyces pombe. Mol Cell Biol 16:1527–1533
Mulvihill DP, Petersen J, Ohkura H, Glover DM, Hagan IM (1999) Plo1 kinase recruitment to the spindle pole body and its role in cell division in Schizosaccharomyces pombe. Mol Biol Cell 10:2771–2785
Murone M, Simanis V (1996) The fission yeast dma1 gene is a component of the spindle assembly checkpoint, required to prevent septum formation and premature exit from mitosis if spindle function is compromised. EMBO J 15:6605–6616
Novak B, Tyson JJ (1993) Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos. J Cell Sci 106:1153–1168
Novak B, Tyson JJ (1997) Modeling the control of DNA replication in fission yeast. Proc Natl Acad Sci USA 94:9147–9152
Novak B, Tyson JJ (2004) A model for restriction point control of the mammalian cell cycle. J Theor Biol 230:563–579
Novak B, Csikasz-Nagy A, Gyorffy B, Chen K, Tyson JJ (1998) Mathematical model of the fission yeast cell cycle with checkpoint controls at the G1/S, G2/M and metaphase/anaphase transitions. Biophys Chem 72:185–200
Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344:503–508
Ohkura H, Hagan IM, Glover DM (1995) The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev 9:1059–1073
Rustici G et al (2004) Periodic gene expression program of the fission yeast cell cycle. Nat Genet 36:809–817
Schmidt S, Sohrmann M, Hofmann K, Woollard A, Simanis V (1997) The Spg1p GTPase is an essential, dosage-dependent inducer of septum formation in Schizosaccharomyces pombe. Genes Dev 11:1519–1534
Simanis V (2003) Events at the end of mitosis in the budding and fission yeasts. J Cell Sci 116:4263–4275
Song K, Mach KE, Chen CY, Reynolds T, Albright CF (1996) A novel suppressor of ras1 in fission yeast, byr4, is a dosage-dependent inhibitor of cytokinesis. J Cell Biol 133:1307–1319
Sparks CA, Morphew M, McCollum D (1999) Sid2p, a spindle pole body kinase that regulates the onset of cytokinesis. J Cell Biol 146:777–790
Stern B, Nurse P (1996) A quantitative model for the cdc2 control of S phase and mitosis in fission yeast. Trends Genet 12:345–350
Sveiczer A, Novak B, Mitchison JM (1996) The size control of fission yeast revisited. J Cell Sci 109(Pt 12):2947–2957
Sveiczer A, Csikasz-Nagy A, Gyorffy B, Tyson JJ, Novak B (2000) Modeling the fission yeast cell cycle: quantized cycle times in wee1- cdc25Delta mutant cells. Proc Natl Acad Sci USA 97:7865–7870
Tanaka K, Petersen J, MacIver F, Mulvihill DP, Glover DM, Hagan IM (2001) The role of Plo1 kinase in mitotic commitment and septation in Schizosaccharomyces pombe. EMBO J 20:1259–1270
Tomlin GC, Morrell JL, Gould KL (2002) The spindle pole body protein Cdc11p links Sid4p to the fission yeast septation initiation network. Mol Biol Cell 13:1203–1214
Trautmann S, Wolfe BA, Jorgensen P, Tyers M, Gould KL, McCollum D (2001) Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression. Curr Biol 11:931–940
Tyson JJ, Chen K, Novak B (2001) Network dynamics and cell physiology. Nat Rev Mol Cell Biol 2:908–916
Tyson JJ, Chen KC, Novak B (2003) Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15:221–231
Wolfe BA, Gould KL (2004a) Fission yeast Clp1p phosphatase affects G(2)/M transition and mitotic exit through Cdc25p inactivation. EMBO J 23:919–929
Wolfe BA, Gould KL (2004b) Inactivating Cdc25, mitotic style. Cell Cycle 3:601–603
Acknowledgments
We are grateful for conversations with colleagues and collaborators: Kathy Chen, Andrea Krapp, Dannel McCollum, Sergio Moreno, Viesturs Simanis, Akos Sveiczer. Funding agencies: Marie Curie Research Training Network (RTN-CT-2004-512348), European Commission (COMBIO: LSHG-CT-2004-503568; YSBN: LSHG-CT-2005-018942), OTKA (F-60414) and the James S. McDonnell Foundation (21002050). A. C-N. is a Bolyai fellow of the Hungarian Academy of Sciences.
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Csikász-Nagy, A., Kapuy, O., Győrffy, B. et al. Modeling the septation initiation network (SIN) in fission yeast cells. Curr Genet 51, 245–255 (2007). https://doi.org/10.1007/s00294-007-0123-4
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DOI: https://doi.org/10.1007/s00294-007-0123-4