Abstract
A modular systems biology approach to the study of the cell cycle of the budding yeast Saccharomyces cerevisiae is presented. Literature on the structure of yeast population and its relevance to the study of yeast cell cycle is reviewed. A model for the control of yeast cell cycle, with emphasis on a threshold mechanism controlling entrance into S-phase is presented. The simple model has been used as a framework to derive a molecular blow-up of the major upstream events controlling the G1 to S transition that involves two sequential thresholds cooperating in carbon source modulation of the critical cell size required to enter S-phase, a hallmark response of the cell cycle to changing growth conditions. The model is discussed as an aid to filter and give structure to post-genomic data. The iterative application of this approach allows to obtain more refined models capturing the major regulatory features and the molecular details of the circuits connecting cell growth to cell cycle.
Preview
Unable to display preview. Download preview PDF.
References
1. Alberghina L, Martegani E, Mariani L, Bortolan G (1983) A bimolecular mechanism for the cell size control of the cell cycle. Biosystems 16:297-305
2. Alberghina L, Porro D (1993) Quantitative flow cytometry: analysis of protein distributions in budding yeast. A mini-review. Yeast 9:815-823
3. Alberghina L, Porro D, Cazzador L (2001) Towards a blueprint of the cell cycle. Oncogene 20:1128-1134
4. Alberghina L, Rossi RL, Querin L, Wanke V, Vanoni M (2004) A cell sizer network involving Cln3 and Far1 controls entrance into S-phase in the mitotic cycle of budding yeast. J Cell Biol 167:433-443
5. Alberghina L, Smeraldi C, Ranzi BM, Porro D (1998) Control by nutrients of growth and cell cycle progression in budding yeast, analyzed by double-tag flow cytometry. J Bacteriol 180:3864-3872
6. Barberis M, DeGioia L, Ruzzene M, Sarno S, Marin O, Coccetti P, Fantucci P, Vanoni M, Alberghina L (2005) Ck2 phosphorylation regulates inhibitory activity of the yeast cyclin dependent kinase inhibitor Sic1. Biochem J Immediate Publication, doi:10.1042/BJ20041299
7. Barr MM (2003) Super models. Physiol Genomics 13:15-24
8. Begley TJ, Rosenbach AS, Ideker T, Samson LD (2002) Damage recovery pathways in Saccharomyces cerevisiae revealed by genomic phenotyping and interactome mapping. Mol Cancer Res 1:103-112
9. Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev MISSING DETAILS?
10. Bugrim A, Nikolskaya T, Nikolsky Y (2004) Early prediction of drug metabolism and toxicity: systems biology approach and modeling. Drug Discov Today 9:127-135
11. Carter BL, Jagadish MN (1978) The relationship between cell size and cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res 112:15-24
12. Castrillo JI, Oliver SG (2004) Yeast as a touchstone in post-genomic research: strategies for integrative analysis in functional genomics. J Biochem Mol Biol 37:93-106
13. Chang F, Herskowitz I (1990) Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2. Cell 63:999-1011
14. 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
15. 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
16. Conzelmann H, Saez-Rodriguez J, Sauter T, Bullinger E, Allgower F, Gilles ED (2004) Reduction of mathematical models of signal transduction networks: simulation-based approach applied to EGF receptor signalling. J Syst Biol 1:159-169
17. Coqueret O (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13:65-70
18. Deane CM, Salwinski L, Xenarios I, Eisenberg D (2002) Protein interactions: two methods for assessment of the reliability of high throughput observations. Mol Cell Proteomics 1:349-356
19. DeRisi JL, Iyer VR, Brown PO (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278:680-686
20. Elion EA (2000) Pheromone response, mating and cell biology. Curr Opin Microbiol 3:573-581
21. Fu X, Ng C, Feng D, Liang C (2003) Cdc48p is required for the cell cycle commitment point at Start via degradation of the G1-CDK inhibitor Far1p. J Cell Biol 163:21-26
22. Futcher B (1996) Cyclins and the wiring of the yeast cell cycle. Yeast 12:1635-1646
23. Gallego C, Gari E, Colomina N, Herrero E, Aldea M (1997) The Cln3 cyclin is down-regulated by translational repression and degradation during the G1 arrest caused by nitrogen deprivation in budding yeast. EMBO J 16:7196-7206
24. Gavin AC, Bosche M, Krause R, Grandi P, Marzioch M, Bauer A, Schultz J, Rick JM, Michon AM, Cruciat CM, Remor M, Hofert C, Schelder M, Brajenovic M, Ruffner H, Merino A, Klein K, Hudak M, Dickson D, Rudi T, Gnau V, Bauch A, Bastuck S, Huhse B, Leutwein C, Heurtier MA, Copley RR, Edelmann A, Querfurth E, Rybin V, Drewes G, Raida M, Bouwmeester T, Bork P, Seraphin B, Kuster B, Neubauer G, Superti-Furga G (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415:141-147
25. Hall DD, Markwardt DD, Parviz F, Heideman W (1998) Regulation of the Cln3-Cdc28 kinase by cAMP in Saccharomyces cerevisiae. EMBO J 17:4370-4378
26. Hartwell LH, Hopfield JJ, Leibler S, Murray AW (1999) From molecular to modular cell biology. Nature 402:C47-C52
27. Hartwell LH, Unger MW (1977) Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division. J Cell Biol 75:422-435
28. Henry CM (2003) Systems Biology. Chem Eng News 81:45-55
29. Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K, Yang L, Wolting C, Donaldson I, Schandorff S, Shewnarane J, Vo M, Taggart J, Goudreault M, Muskat B, Alfarano C, Dewar D, Lin Z, Michalickova K, Willems AR, Sassi H, Nielsen PA, Rasmussen KJ, Andersen JR, Johansen LE, Hansen LH, Jespersen H, Podtelejnikov A, Nielsen E, Crawford J, Poulsen V, Sorensen BD, Matthiesen J, Hendrickson RC, Gleeson F, Pawson T, Moran MF, Durocher D, Mann M, Hogue CW, Figeys D, Tyers M (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415:180-183
30. Hubler L, Bradshaw-Rouse J, Heideman W (1993) Connections between the Ras-cyclic AMP pathway and G1 cyclin expression in the budding yeast Saccharomyces cerevisiae. Mol Cell Biol 13:6274-6282
31. Ingolia NT Murray AW(2004) The ups and downs of modeling the cell cycle. Curr Biol 14:R771-R777
32. Ito T, Ota K, Kubota H, Yamaguchi Y, Chiba T, Sakuraba K, Yoshida M (2002) Roles for the two-hybrid system in exploration of the yeast protein interactome. Mol Cell Proteomics 1:561-566
33. Iyer VR, Horak CE, Scafe CS, Botstein D, Snyder M, Brown PO (2001) Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409:533-538
34. Jeoung DI, Oehlen LJ, Cross FR (1998) Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway. Mol Cell Biol 18:433-441
35. Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297:395-400
36. Jorgensen P, Tyers M (2004) How cells coordinate growth and division. Curr Biol 14:R1014-1027
37. Kahn D, Westerhoff HV (1991) Control theory of regulatory cascades. J Theor Biol 153:255-85
38. Kitano H (2002a) Looking beyond the details: a rise in system-oriented approaches in genetics and molecular biology. Curr Genet 41:1-10
39. Kitano H (2002b) Systems biology: a brief overview. Science 295:1662-1664
40. Kitano H (2004a) Biological robustness. Nat Rev Genet 5: 826-837
41. Kitano H (2004b) Cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer 4:227-235
42. Lee MG, Nurse P (1987) Cell cycle genes of the fission yeast. Sci Prog 71:1-14
43. Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne JB, Volkert TL, Fraenkel E, Gifford DK, Young RA (2002) Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298:799-804
44. Li F, Long T, Lu Y, Ouyang Q, Tang C (2004) The yeast cell-cycle network is robustly designed. Proc Natl Acad Sci USA 101:4781-4786
45. Lord PG, Wheals AE (1980) Asymmetrical division of Saccharomyces cerevisiae. J Bacteriol 142:808-818
46. Martegani E, Vanoni M, Delia D (1984) A computer algorithm for the analysis of protein distribution in budding yeast. Cytometry 5:81-85
47. Mendenhall MD (1993) An inhibitor of p34CDC28 protein kinase activity from Saccharomyces cerevisiae. Science 259:216-219
48. Mendenhall MD, Hodge AE (1998) Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 62:1191-1243
49. Morgan DO (1995) Principles of CDK regulation. Nature 374:131-134
50. Morohashi M, Winn AE, Borisuk MT, Bolouri H, Doyle J, Kitano H (2002) Robustness as a measure of plausibility in models of biochemical networks. J Theor Biol 216:19-30
51. Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116:221-234
52. Newcomb LL, Diderich JA, Slattery MG, Heideman W (2003) Glucose regulation of Saccharomyces cerevisiae cell cycle genes. Eukaryot Cell 2:143-149
53. Nise NS (2004) Control Systems Engineering, 4th edn. John Wiley & Son, Inc.
54. Nurse P (2000) The incredible life and times of biological cells. Science 289:1711-1716
55. Nurse P (2003) Systems biology: understanding cells. Nature 424:883
56. Obaya AJ, Sedivy JM (2002) Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci 59:126-142
57. Peter M, Gartner A, Horecka J, Ammerer G, Herskowitz I (1993) FAR1 links the signal transduction pathway to the cell cycle machinery in yeast. Cell 73:747-760
58. Peter M, Herskowitz I (1994) Direct inhibition of the yeast cyclin-dependent kinase Cdc28-Cln by Far1. Science 265:1228-1231
59. Porro D, Brambilla L, Alberghina L (2003) Glucose metabolism and cell size in continuous cultures of Saccharomyces cerevisiae. FEMS Microbiol Lett 229:165-171
60. Porro D, Ranzi BM, Smeraldi C, Martegani E, Alberghina L (1995) A double flow cytometric tag allows tracking of the dynamics of cell cycle progression of newborn Saccharomyces cerevisiae cells during balanced exponential growth. Yeast 11:1157-1169
61. Ranzi BM, Compagno C, Martegani E (1986) Analysis of protein and cell volume distribution in glucose-limited continuous cultures of budding yeast. Biotechnol Bioeng 28:185-190
62. Rossell S, van der Weijden CC, Kruckeberg A, Bakker BM, Westerhoff HV (2002) Loss of fermentative capacity in baker's yeast can partly be explained by reduced glucose uptake capacity. Mol Biol Rep 29:255-257
63. Rupes I (2002) Checking cell size in yeast. Trends Genet 18:479-485
64. Russell RB (2002) Genomics, proteomics and bioinformatics: all in the same boat. Genome Biol 3:REPORTS4034
65. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP (1996) Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382:325-331
66. Sauro HM, Hucka M, Finney A, Wellock C, Bolouri H, Doyle J, Kitano H (2003) Next generation simulation tools: the Systems Biology Workbench and BioSPICE integration. Omics 7:355-372
67. Schneider BL, Zhang J, Markwardt J, Tokiwa G, Volpe T, Honey S, Futcher B (2004) Growth rate and cell size modulate the synthesis of, and requirement for, G1-phase cyclins at start. Mol Cell Biol 24:10802-10813
68. Schuster S, Kahn D, Westerhoff HV (1993) Modular analysis of the control of complex metabolic pathways. Biophys Chem 48:1-17
69. Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B (1998) Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol Biol Cell 9:3273-3297
70. Stelling J, Sauer U, Szallasi Z, Doyle FJ 3rd, Doyle J (2004) Robustness of cellular functions. Cell 118: 675-685
71. Tapon N, Moberg KH, Hariharan IK (2001) The coupling of cell growth to the cell cycle. Curr Opin Cell Biol 13:731-737
72. Tyson CB, Lord PG, Wheals AE (1979) Dependency of size of Saccharomyces cerevisiae cells on growth rate. J Bacteriol 138:92-98
73. Tyson JJ (1989) Effects of asymmetric division on a stochastic model of the cell division cycle. Math Biosci 96:165-184
74. 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
75. Tyers M, Tokiwa G, Futcher B (1993) Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J 12:1955-1968
76. Uetz P, Giot L, Cagney G, Mansfield TA, Judson RS, Knight JR, Lockshon D, Narayan V, Srinivasan M, Pochart P, Qureshi-Emili A, Li Y, Godwin B, Conover D, Kalbfleisch T, Vijayadamodar G, Yang M, Johnston M, Fields S, Rothberg JM (2000) A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403:623-627
77. Valtz N, Peter M, Herskowitz I (1995) FAR1 is required for oriented polarization of yeast cells in response to mating pheromones. J Cell Biol 131:863-873
78. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899-5912
79. Vanoni M, Vai M, Popolo L, Alberghina L (1983) Structural heterogeneity in populations of the budding yeast Saccharomyces cerevisiae. J Bacteriol 156:1282-1291
80. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131-149
81. Wells WA (2002) Does size matter? J Cell Biol 158:1156-1159
82. Werner T (2004) Proteomics and regulomics: the yin and yang of functional genomics. Mass Spectrom Rev 23:25-33
83. Werner T, Fessele S, Maier H, Nelson PJ (2003) Computer modeling of promoter organization as a tool to study transcriptional coregulation. FASEB J 17:1228-1237
84. Westerhoff HV Palsson BO (2004) The evolution of molecular biology into systems biology. Nat Biotechnol 22:1249-1252
85. Vidal M (2001) A biological atlas of functional maps. Cell 104:333-339
86. Wiley HS, Shvartsman SY, Lauffenburger DA (2003) Computational modeling of the EGF-receptor system: a paradigm for systems biology. Trends Cell Biol 13:43-50
87. Willett JD (2002) Genomics, proteomics: What's next? Pharmacogenomics 3:727-728
88. Woldringh CL, Huls PG, Vischer NO (1993) Volume growth of daughter and parent cells during the cell cycle of Saccharomyces cerevisiae a/alpha as determined by image cytometry. J Bacteriol 175:3174-3181
89. Yarmush ML, Banta S (2003) Metabolic engineering: advances in modeling and intervention in health and disease. Annu Rev Biomed Eng 5:349-381
90. Yi TM, Kitano H, Simon MI (2003) A quantitative characterization of the yeast heterotrimeric G protein cycle. Proc Natl Acad Sci USA 100:10764-10769
Author information
Authors and Affiliations
Corresponding author
Editor information
Rights and permissions
About this chapter
Cite this chapter
Alberghina, L., Rossi, R.L., Porro, D., Vanoni, M. A modular systems biology analysis of cell cycle entrance into S-phase. In: Alberghina, L., Westerhoff, H. (eds) Systems Biology. Topics in Current Genetics, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b138746
Download citation
DOI: https://doi.org/10.1007/b138746
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-22968-1
Online ISBN: 978-3-540-31453-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)