The effective application of a discrete transition model to explore cell-cycle regulation in yeast

BMC Research Notes

Yona Kassir¹  Ron Y Pinter²  Benny Chor³  Ofir Hazan⁴  Amir Rubinstein³ 

[1]Department of Biology, Technion – Israel Institute of Technology, Haifa 3200003, Israel

[2]Department of Computer Science, Technion – Israel Institute of Technology, Haifa 3200003, Israel

[3]School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel

[4]Department of Mathematics, Ort Braude College, Karmiel 21982, Israel

关键词: Simulation;    Regulatory networks;    Computational model;    Budding yeast;    Commitment;    Cell-cycle;   

Others  :  1141949
DOI  :  10.1186/1756-0500-6-311

 received in 2013-07-21, accepted in 2013-07-31,  发布年份 2013

【 摘 要 】

Background

Bench biologists often do not take part in the development of computational models for their systems, and therefore, they frequently employ them as “black-boxes”. Our aim was to construct and test a model that does not depend on the availability of quantitative data, and can be directly used without a need for intensive computational background.

Results

We present a discrete transition model. We used cell-cycle in budding yeast as a paradigm for a complex network, demonstrating phenomena such as sequential protein expression and activity, and cell-cycle oscillation. The structure of the network was validated by its response to computational perturbations such as mutations, and its response to mating-pheromone or nitrogen depletion. The model has a strong predicative capability, demonstrating how the activity of a specific transcription factor, Hcm1, is regulated, and what determines commitment of cells to enter and complete the cell-cycle.

Conclusion

The model presented herein is intuitive, yet is expressive enough to elucidate the intrinsic structure and qualitative behavior of large and complex regulatory networks. Moreover our model allowed us to examine multiple hypotheses in a simple and intuitive manner, giving rise to testable predictions. This methodology can be easily integrated as a useful approach for the study of networks, enriching experimental biology with computational insights.

【 授权许可】

   
2013 Rubinstein et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Freeman M: Feedback control of intercellular signalling in development. Nat Geosci 2000, 408(6810):313-319.
• [2]Smolen P, Baxter DA, Byrne JH: Mathematical modeling of gene networks. Neuron 2000, 26(3):567-580.
• [3]Karlebach G, Shamir R: Modelling and analysis of gene regulatory networks. Nat Rev Mol Cell Biol 2008, 9(10):770-780.
• [4]Mogilner A, Allard J, Wollman R: Cell polarity: quantitative modeling as a tool in cell biology. Science 2012, 336(6078):175-179.
• [5]Morelli LG, Uriu K, Ares S, Oates AC: Computational approaches to developmental patterning. Science 2012, 336(6078):187-191.
• [6]Munsky B, Neuert G, van Oudenaarden A: Using gene expression noise to understand gene regulation. Science 2012, 336(6078):183-187.
• [7]Rubinstein A, Gurevich V, Kasulin-Boneh Z, Pnueli L, Kassir Y, Pinter RY: Faithful modeling of transient expression and its application to elucidating negative feedback regulation. Proc Natl Acad Sci U S A 2007, 104(15):6241-6246.
• [8]Schaub MA, Henzinger TA, Fisher J: Qualitative networks: a symbolic approach to analyze biological signaling networks. BMC Syst Biol 2007, 1:4. BioMed Central Full Text
• [9]Hartwell LH, Culotti J, Pringle JR, Reid BJ: Genetic control of the cell division cycle in yeast. Science 1974, 183(4120):46-51.
• [10]Zhou BB, Elledge SJ: The DNA damage response: putting checkpoints in perspective. Nat Geosci 2000, 408(6811):433-439.
• [11]Nasmyth K: At the heart of the budding yeast cell cycle. Trends Genet 1996, 12(10):405-412.
• [12]Morgan DO: Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 1997, 13:261-291.
• [13]Pramila T, Wu W, Miles S, Noble WS, Breeden LL: The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle. Genes Dev 2006, 20(16):2266-2278.
• [14]Weinreich M, Liang C, Stillman B: The Cdc6p nucleotide-binding motif is required for loading mcm proteins onto chromatin. Proc Natl Acad Sci USA 1999, 96(2):441-446.
• [15]Piatti S, Lengauer C, Nasmyth K: Cdc6 is an unstable protein whose de novo synthesis in G1 is important for the onset of S phase and for preventing a 'reductional' anaphase in the budding yeast Saccharomyces cerevisiae. Embo J 1995, 14(15):3788-3799.
• [16]Cocker JH, Piatti S, Santocanale C, Nasmyth K, Diffley JF: An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast. Nat Geosci 1996, 379(6561):180-182.
• [17]Tanaka T, Knapp D, Nasmyth K: Loading of an Mcm protein onto DNA replication origins is regulated by Cdc6p and CDKs. Cell 1997, 90(4):649-660.
• [18]Hartwell L: Sequential function of gene products relative to DNA synthesis in the yeast cell cycle. J Mol Biol 1976, 104(4):803-817.
• [19]Richardson H, Lew DJ, Henze M, Sugimoto K, Reed SI: Cyclin-B homologs in Saccharomyces cerevisiae function in S phase and in G2. Genes Dev 1992, 6(11):2021-2034.
• [20]Visintin R, Prinz S, Amon A: CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science 1997, 278(5337):460-463.
• [21]Wasch R, Cross FR: APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit. Nat Geosci 2002, 418(6897):556-562.
• [22]Rudner AD, Murray AW: Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex. J Cell Biol 2000, 149(7):1377-1390.
• [23]Irniger S, Nasmyth K: The anaphase-promoting complex is required in G1 arrested yeast cells to inhibit B-type cyclin accumulation and to prevent uncontrolled entry into S-phase. J Cell Sci 1997, 110(13):1523-1531.
• [24]Peter M, Herskowitz I: Direct inhibition of the yeast cyclin-dependent kinase Cdc28-Cln by Far1. Science 1994, 265(5176):1228-1231.
• [25]Jeoung DI, Oehlen LJ, Cross FR: Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway. Mol Cell Biol 1998, 18(1):433-441.
• [26]Tyers M, Futcher B: Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes. Mol Cell Biol 1993, 13(9):5659-5669.
• [27]Dirick L, Nasmyth K: Positive feedback in the activation of G1 cyclins in yeast. Nat Geosci 1991, 351(6329):754-757.
• [28]Stuart D, Wittenberg C: CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. Genes Dev 1995, 9(22):2780-2794.
• [29]Skotheim JM, Di Talia S, Siggia ED, Cross FR: Positive feedback of G1 cyclins ensures coherent cell cycle entry. Nat Geosci 2008, 454(7202):291-296.
• [30]Schwob E, Bohm T, Mendenhall MD, Nasmyth K: The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 1994, 79(2):233-244.
• [31]Pathak R, Blank HM, Guo J, Ellis S, Polymenis M: The Dcr2p phosphatase destabilizes Sic1p in Saccharomyces cerevisiae. Biochem Biophys Res Commun 2007, 361(3):700-704.
• [32]Tyers M: The cyclin-dependent kinase inhibitor p40SIC1 imposes the requirement for Cln G1 cyclin function at Start. Proc Natl Acad Sci USA 1996, 93(15):7772-7776.
• [33]Nishizawa M, Kawasumi M, Fujino M, Toh-e A: Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. Mol Biol Cell 1998, 9(9):2393-2405.
• [34]Doncic A, Falleur-Fettig M, Skotheim JM: Distinct interactions select and maintain a specific cell fate. Mol Cell 2011, 43(4):528-539.
• [35]Henchoz S, Chi Y, Catarin B, Herskowitz I, Deshaies RJ, Peter M: Phosphorylation- and ubiquitin-dependent degradation of the cyclin- dependent kinase inhibitor Far1p in budding yeast. Genes Dev 1997, 11(22):3046-3060.
• [36]Pringle JR, Hartwell LH: The Saccharomyces cerevisiae cell cycle. In The Molecular Biology of the Yeast Saccharomyces cerevisiae. Edited by Strathern JN, Jones EW, Broach JR. Cold Spring Harbor: Life Cycle and Inheritance Cold Spring Harbor Laboratory Press; 1981:97-142. ISBN I
• [37]Gallego C, Gari E, Colomina N, Herrero E, Aldea M: The Cln3 cyclin is down-regulated by translational repression and degradation during the G1 arrest caused by nitrogen deprivation in budding yeast. EMBO J 1997, 16(23):7196-7206.
• [38]Wang H, Gari E, Verges E, Gallego C, Aldea M: Recruitment of Cdc28 by Whi3 restricts nuclear accumulation of the G1 cyclin-Cdk complex to late G1. EMBO J 2004, 23(1):180-190.
• [39]Hadwiger JA, Wittenberg C, Richardson HE, de Barros LM, Reed SI: A family of cyclin homologs that control the G1 phase in yeast. Proc Natl Acad Sci U S A 1989, 86(16):6255-6259.
• [40]Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO: Targets of the cyclin-dependent kinase Cdk1. Nat Geosci 2003, 425(6960):859-864.
• [41]Fawcett TW, Higginson AD: Heavy use of equations impedes communication among biologists. Proc Natl Acad Sci USA 2012, 109(29):11735-11739.
• [42]May RM: Uses and abuses of mathematics in biology. Science 2004, 303(5659):790-793.
• [43]Pramila T, Miles S, GuhaThakurta D, Jemiolo D, Breeden LL: Conserved homeodomain proteins interact with MADS box protein Mcm1 to restrict ECB-dependent transcription to the M/G1 phase of the cell cycle. Genes Dev 2002, 16(23):3034-3045.
• [44]Polymenis M, Schmidt EV: Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. Genes Dev 1997, 11(19):2522-2531.
• [45]Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN: TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 1996, 7(1):25-42.
• [46]Yaglom J, Linskens MH, Sadis S, Rubin DM, Futcher B, Finley D: p34Cdc28-mediated control of Cln3 cyclin degradation. Mol Cell Biol 1995, 15(2):731-741.
• [47]de Bruin RA, McDonald WH, Kalashnikova TI, Yates J 3rd, Wittenberg C: Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 2004, 117(7):887-898.
• [48]Andrews BJ, Herskowitz I: Identification of a DNA binding factor involved in cell-cycle control of the yeast HO gene. Cell 1989, 57(1):21-29.
• [49]Nasmyth K, Dirick L: The role of SW14 and SW16 in the activity of G1 cyclins in yeast. Cell 1991, 66(5):995-1013.
• [50]Eser U, Falleur-Fettig M, Johnson A, Skotheim JM: Commitment to a cellular transition precedes genome-wide transcriptional change. Mol Cell 2011, 43(4):515-527.
• [51]Koch C, Schleiffer A, Ammerer G, Nasmyth K: Switching transcription on and off during the yeast cell cycle: Cln/Cdc28 kinases activate bound transcription factor SBF (Swi4/Swi6) at start, whereas Clb/Cdc28 kinases displace it from the promoter in G2. Genes Dev 1996, 10(2):129-141.
• [52]Geymonat M, Spanos A, Wells GP, Smerdon SJ, Sedgwick SG: Clb6/Cdc28 and Cdc14 regulate phosphorylation status and cellular localization of Swi6. Mol Cell Biol 2004, 24(6):2277-2285.
• [53]Iyer VR, Horak CE, Scafe CS, Botstein D, Snyder M, Brown PO: Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nat Geosci 2001, 409(6819):533-538.
• [54]Bean JM, Siggia ED, Cross FR: High functional overlap between MluI cell-cycle box binding factor and Swi4/6 cell-cycle box binding factor in the G1/S transcriptional program in Saccharomyces cerevisiae. Genetics 2005, 171(1):49-61.
• [55]Ogas J, Andrews BJ, Herskowitz I: Transcriptional activation of CLN1, CLN2, and a putative new G1 cyclin (HCS26) by SWI4, a positive regulator of G1-specific transcription. Cell 1991, 66(5):1015-1026.
• [56]de Bruin RA, Kalashnikova TI, Chahwan C, McDonald WH, Wohlschlegel J, Yates J 3rd, Russell P, Wittenberg C: Constraining G1-specific transcription to late G1 phase: the MBF-associated corepressor Nrm1 acts via negative feedback. Mol Cell 2006, 23(4):483-496.
• [57]Ostapenko D, Solomon MJ: Anaphase promoting complex-dependent degradation of transcriptional repressors Nrm1 and Yhp1 in Saccharomyces cerevisiae. Mol Biol Cell 2011, 22(13):2175-2184.
• [58]Sari F, Braus GH, Irniger S: A process independent of the anaphase-promoting complex contributes to instability of the yeast S phase cyclin Clb5. J Biol Chem 2007, 282(36):26614-26622.
• [59]Piatti S, Bohm T, Cocker JH, Diffley JF, Nasmyth K: Activation of S-phase-promoting CDKs in late G1 defines a “point of no return” after which Cdc6 synthesis cannot promote DNA replication in yeast. Genes Dev 1996, 10(12):1516-1531.
• [60]Drury LS, Perkins G, Diffley JF: The cyclin-dependent kinase Cdc28p regulates distinct modes of Cdc6p proteolysis during the budding yeast cell cycle. Curr Biol 2000, 10(5):231-240.
• [61]Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B: Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol Biol Cell 1998, 9(12):3273-3297.
• [62]Nougarede R, Della Seta F, Zarzov P, Schwob E: Hierarchy of S-phase-promoting factors: yeast Dbf4-Cdc7 kinase requires prior S-phase cyclin-dependent kinase activation. Mol Cell Biol 2000, 20(11):3795-3806.
• [63]Bell SP, Dutta A: DNA replication in eukaryotic cells. Annu Rev Biochem 2002, 71:333-374.
• [64]Owens JC, Detweiler CS, Li JJ: CDC45 is required in conjunction with CDC7/DBF4 to trigger the initiation of DNA replication. Proc Natl Acad Sci USA 1997, 94(23):12521-12526.
• [65]Pic-Taylor A, Darieva Z, Morgan BA, Sharrocks AD: Regulation of cell cycle-specific gene expression through cyclin-dependent kinase-mediated phosphorylation of the forkhead transcription factor Fkh2p. Mol Cell Biol 2004, 24(22):10036-10046.
• [66]Veis J, Klug H, Koranda M, Ammerer G: Activation of the G2/M-specific gene CLB2 requires multiple cell cycle signals. Mol Cell Biol 2007, 27(23):8364-8373.
• [67]Kumar R, Reynolds DM, Shevchenko A, Goldstone SD, Dalton S: Forkhead transcription factors, Fkh1p and Fkh2p, collaborate with Mcm1p to control transcription required for M-phase. Curr Biol 2000, 10(15):896-906.
• [68]Koranda M, Schleiffer A, Endler L, Ammerer G: Forkhead-like transcription factors recruit Ndd1 to the chromatin of G2/M-specific promoters. Nat Geosci 2000, 406(6791):94-98.
• [69]Kishi T, Ikeda A, Koyama N, Fukada J, Nagao R: A refined two-hybrid system reveals that SCF(Cdc4)-dependent degradation of Swi5 contributes to the regulatory mechanism of S-phase entry. Proc Natl Acad Sci U S A 2008, 105(38):14497-14502.
• [70]Cross FR: Two redundant oscillatory mechanisms in the yeast cell cycle. Dev Cell 2003, 4(5):741-752.
• [71]Knapp D, Bhoite L, Stillman DJ, Nasmyth K: The transcription factor Swi5 regulates expression of the cyclin kinase inhibitor p40SIC1. Mol Cell Biol 1996, 16(10):5701-5707.
• [72]Cohen-Fix O, Peters JM, Kirschner MW, Koshland D: Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. Genes Dev 1996, 10(24):3081-3093.
• [73]Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M, Nasmyth K: An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 1998, 93(6):1067-1076.
• [74]Jaspersen S, Charles JF, Morgan DO: Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr Biol 1999, 9(5):227-236.
• [75]Visintin C, Tomson BN, Rahal R, Paulson J, Cohen M, Taunton J, Amon A, Visintin R: APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. Genes Dev 2008, 22(1):79-90.
• [76]Chang F, Herskowitz I: 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 1990, 63(5):999-1011.