Key Points
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In budding yeast, multiple cyclins activate a single cyclin-dependent kinase (Cdk) to control progression through the cell cycle.
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The ability of specific cyclins to target Cdk to different substrates reflects the timing of expression of individual cyclins in some cases, and in others it reflects the intrinsic properties of individual cyclin proteins.
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Mechanisms that lead to cyclin specificity include transcriptional activation, proteolysis, negative regulation by particular inhibitors, subcellular localization and binding to specific substrates.
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Intrinsic cyclin-specific properties affect both the regulation of cyclins as well as the targeting of particular substrates to control downstream events; signal-transduction pathways have evolved to exploit cyclin specificity to produce cell-cycle-specific responses to specific signals.
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The specificity of different cyclins is thought to be important for the proper order and timing of cell-cycle events.
Abstract
Cyclins regulate the cell cycle by binding to and activating cyclin-dependent kinases (Cdks). Phosphorylation of specific targets by cyclin–Cdk complexes sets in motion different processes that drive the cell cycle in a timely manner. In budding yeast, a single Cdk is activated by multiple cyclins. The ability of these cyclins to target specific proteins and to initiate different cell-cycle events might, in some cases, reflect the timing of the expression of the cyclins; in others, it might reflect intrinsic properties of the cyclins that render them better suited to target particular proteins.
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References
Cross, F. R., Archambault, V., Miller, M. & Klovstad, M. Testing a mathematical model of the yeast cell cycle. Mol. Biol. Cell 13, 52–70 (2002).
Loog, M. & Morgan, D. O. Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature 434, 104–108 (2005). Identifies Cdc28 substrates that are preferentially phosphorylated by Clb5-directed Cdc28.
Haase, S. B. & Reed, S. I. Evidence that a free-running oscillator drives G1 events in the budding yeast cell cycle. Nature 401, 394–397 (1999).
Hu, F. & Aparicio, O. M. Swe1 regulation and transcriptional control restrict the activity of mitotic cyclins toward replication proteins in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 102, 8910–8915 (2005).
Epstein, C. B. & Cross, F. R. CLB5: a novel B cyclin from budding yeast with a role in S phase. Genes Dev. 6, 1695–1706 (1992).
Tyers, M. The cyclin-dependent kinase inhibitor p40SIC1 imposes the requirement for Cln G1 cyclin function at Start. Proc. Natl Acad. Sci. USA 93, 7772–7776 (1996).
Fisher, D. L. & Nurse, P. A single fission yeast mitotic cyclin B p34cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins. EMBO J. 15, 850–860 (1996).
Levine, K., Kiang, L., Jacobson, M. D., Fisher, R. P. & Cross, F. R. Directed evolution to bypass cyclin requirements for the Cdc28p cyclin-dependent kinase. Mol. Cell 4, 353–363 (1999).
Cross, F. R., Yuste-Rojas, M., Gray, S. & Jacobson, M. D. Specialization and targeting of B-type cyclins. Mol. Cell 4, 11–19 (1999).
Jacobson, M. D., Gray, S., Yuste-Rojas, M. & Cross, F. R. Testing cyclin specificity in the exit from mitosis. Mol. Cell. Biol. 20, 4483–4493 (2000).
Archambault, V. et al. Targeted proteomic study of the cyclin–cdk module. Mol. Cell 14, 699–711 (2004). Identifies upstream regulators and downstream targets of individual cyclin–Cdc28 complexes by mass-spectrometric analysis.
Cross, F. R. & Jacobson, M. D. Conservation and function of a potential substrate-binding domain in the yeast Clb5 B-type cyclin. Mol. Cell. Biol. 20, 4782–4790 (2000).
Nasmyth, K. & Dirick, L. The role of SWI4 and SWI6 in the activity of G1 cyclins in yeast. Cell 66, 995–1013 (1991).
Ogas, J., Andrews, B. J. & Herskowitz, I. Transcriptional activation of CLN1, CLN2, and a putative new G1 cyclin (HCS26) by SWI4, a positive regulator of G1-specific transcription. Cell 66, 1015–1026 (1991).
Schwob, E. & Nasmyth, K. CLB5 and CLB6, a new pair of B cyclins involved in DNA replication in Saccharomyces cerevisiae. Genes Dev. 7, 1160–1175 (1993).
Bean, J. M., Siggia, E. D. & Cross, F. R. 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 171, 49–61 (2005).
Tyers, M., Tokiwa, G. & Futcher, B. Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J. 12, 1955–1968 (1993).
Dirick, L., Bohm, T. & Nasmyth, K. Roles and regulation of Cln–Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae. EMBO J. 14, 4803–4813 (1995).
Stuart, D. & Wittenberg, C. CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. Genes Dev. 9, 2780–2794 (1995).
Levine, K., Huang, K. & Cross, F. R. Saccharomyces cerevisiae G1 cyclins differ in their intrinsic functional specificities. Mol. Cell. Biol. 16, 6794–6803 (1996).
de Bruin, R. A., McDonald, W. H., Kalashnikova, T. I., Yates, J. 3rd & Wittenberg, C. Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 117, 887–898 (2004).
Costanzo, M. et al. CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 117, 899–913 (2004). References 21 and 22 describe Cln–Cdc28-dependent phosphorylation of the SBF inhibitor Whi5, which allows for the transcription of CLN1 and CLN2.
Cross, F. R. & Tinkelenberg, A. H. A potential positive feedback loop controlling CLN1 and CLN2 gene expression at the start of the yeast cell cycle. Cell 65, 875–883 (1991).
Dirick, L. & Nasmyth, K. Positive feedback in the activation of G1 cyclins in yeast. Nature 351, 754–757 (1991).
Geymonat, M., Spanos, A., Wells, G. P., Smerdon, S. J. & Sedgwick, S. G. Clb6/Cdc28 and Cdc14 regulate phosphorylation status and cellular localization of Swi6. Mol. Cell. Biol. 24, 2277–2285 (2004).
Amon, A., Tyers, M., Futcher, B. & Nasmyth, K. Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins. Cell 74, 993–1007 (1993).
Siegmund, R. F. & Nasmyth, K. A. The Saccharomyces cerevisiae Start-specific transcription factor Swi4 interacts through the ankyrin repeats with the mitotic Clb2/Cdc28 kinase and through its conserved carboxy terminus with Swi6. Mol. Cell. Biol. 16, 2647–2655 (1996).
Fitch, I. et al. Characterization of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae. Mol. Biol. Cell 3, 805–818 (1992).
Reynolds, D. et al. Recruitment of Thr319-phosphorylated Ndd1p to the FHA domain of Fkh2p requires Clb kinase activity: a mechanism for CLB cluster gene activation. Genes Dev. 17, 1789–1802 (2003).
Darieva, Z. et al. Cell cycle-regulated transcription through the FHA domain of Fkh2p and the coactivator Ndd1p. Curr. Biol. 13, 1740–1745 (2003).
Pic-Taylor, A., Darieva, Z., Morgan, B. A. & Sharrocks, A. D. Regulation of cell cycle-specific gene expression through cyclin-dependent kinase-mediated phosphorylation of the forkhead transcription factor Fkh2p. Mol. Cell. Biol. 24, 10036–10046 (2004).
Barral, Y., Jentsch, S. & Mann, C. G1 cyclin turnover and nutrient uptake are controlled by a common pathway in yeast. Genes Dev. 9, 399–409 (1995).
Skowyra, D., Craig, K. L., Tyers, M., Elledge, S. J. & Harper, J. W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91, 209–219 (1997).
Jackson, L. P., Reed, S. I. & Haase, S. B. Distinct mechanisms control the stability of the related S-phase cyclins Clb5 and Clb6. Mol. Cell. Biol. 26, 2456–2466 (2006).
Donaldson, A. D. et al. CLB5-dependent activation of late replication origins in S. cerevisiae. Mol. Cell 2, 173–182 (1998).
Peters, J. M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nature Rev. Mol. Cell Biol. 7, 644–656 (2006).
Shirayama, M., Toth, A., Galova, M. & Nasmyth, K. APCCdc20 promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5. Nature 402, 203–207 (1999).
Wasch, R. & Cross, F. R. APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit. Nature 418, 556–562 (2002).
Rudner, A. D. & Murray, A. W. Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex. J. Cell Biol. 149, 1377–1390 (2000).
Zachariae, W., Schwab, M., Nasmyth, K. & Seufert, W. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282, 1721–1724 (1998).
Jaspersen, S. L., Charles, J. F. & Morgan, D. O. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr. Biol. 9, 227–236 (1999).
Yeong, F. M., Lim, H. H., Wang, Y. & Surana, U. Early expressed Clb proteins allow accumulation of mitotic cyclin by inactivating proteolytic machinery during S phase. Mol. Cell. Biol. 21, 5071–5081 (2001).
Huang, J. N., Park, I., Ellingson, E., Littlepage, L. E. & Pellman, D. Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p. J. Cell Biol. 154, 85–94 (2001).
Schwob, E., Bohm, T., Mendenhall, M. D. & Nasmyth, K. The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 79, 233–244 (1994).
Feldman, R. M., Correll, C. C., Kaplan, K. B. & Deshaies, R. J. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91, 221–230 (1997).
Verma, R. et al. Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. Science 278, 455–460 (1997).
Miller, M. E. & Cross, F. R. Distinct subcellular localization patterns contribute to functional specificity of the Cln2 and Cln3 cyclins of Saccharomyces cerevisiae. Mol. Cell. Biol. 20, 542–555 (2000).
Miller, M. E. & Cross, F. R. Mechanisms controlling subcellular localization of the G1 cyclins Cln2p and Cln3p in budding yeast. Mol. Cell. Biol. 21, 6292–6311 (2001).
Edgington, N. P. & Futcher, B. Relationship between the function and the location of G1 cyclins in S. cerevisiae. J. Cell Sci. 114, 4599–4611 (2001).
Bailly, E., Cabantous, S., Sondaz, D., Bernadac, A. & Simon, M. N. Differential cellular localization among mitotic cyclins from Saccharomyces cerevisiae: a new role for the axial budding protein Bud3 in targeting Clb2 to the mother-bud neck. J. Cell Sci. 116, 4119–4130 (2003).
Hood, J. K., Hwang, W. W. & Silver, P. A. The Saccharomyces cerevisiae cyclin Clb2p is targeted to multiple subcellular locations by cis- and trans-acting determinants. J. Cell Sci. 114, 589–597 (2001).
Booher, R. N., Deshaies, R. J. & Kirschner, M. W. Properties of Saccharomyces cerevisiae Wee1 and its differential regulation of p34CDC28 in response to G1 and G2 cyclins. EMBO J. 12, 3417–3426 (1993).
Thornton, B. R. & Toczyski, D. P. Securin and B-cyclin/CDK are the only essential targets of the APC. Nature Cell Biol. 5, 1090–1094 (2003).
Asano, S. et al. Concerted mechanism of Swe1/Wee1 regulation by multiple kinases in budding yeast. EMBO J. 24, 2194–2204 (2005).
Harvey, S. L., Charlet, A., Haas, W., Gygi, S. P. & Kellogg, D. R. Cdk1-dependent regulation of the mitotic inhibitor Wee1. Cell 122, 407–420 (2005).
Breitkreutz, A. & Tyers, M. MAPK signaling specificity: it takes two to tango. Trends Cell Biol. 12, 254–257 (2002).
Peter, M. & Herskowitz, I. Direct inhibition of the yeast cyclin-dependent kinase Cdc28–Cln by Far1. Science 265, 1228–1231 (1994).
Jeoung, D. I., Oehlen, L. J. & Cross, F. R. Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway. Mol. Cell. Biol. 18, 433–441 (1998).
Gartner, A. et al. Pheromone-dependent G1 cell cycle arrest requires Far1 phosphorylation, but may not involve inhibition of Cdc28–Cln2 kinase, in vivo. Mol. Cell. Biol. 18, 3681–3691 (1998).
McKinney, J. D., Chang, F., Heintz, N. & Cross, F. R. Negative regulation of FAR1 at the Start of the yeast cell cycle. Genes Dev. 7, 833–843 (1993).
Henchoz, S. et al. Phosphorylation- and ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor Far1p in budding yeast. Genes Dev. 11, 3046–3060 (1997).
McKinney, J. D. & Cross, F. R. FAR1 and the G1 phase specificity of cell cycle arrest by mating factor in Saccharomyces cerevisiae. Mol. Cell. Biol. 15, 2509–2516 (1995).
Oehlen, L. J., Jeoung, D. I. & Cross, F. R. Cyclin-specific START events and the G1-phase specificity of arrest by mating factor in budding yeast. Mol. Gen. Genet. 258, 183–198 (1998).
Oehlen, L. J. & Cross, F. R. G1 cyclins CLN1 and CLN2 repress the mating factor response pathway at Start in the yeast cell cycle. Genes Dev. 8, 1058–1070 (1994).
Oehlen, L. J. & Cross, F. R. Potential regulation of Ste20 function by the Cln1–Cdc28 and Cln2–Cdc28 cyclin-dependent protein kinases. J. Biol. Chem. 273, 25089–25097 (1998).
Wu, C., Leeuw, T., Leberer, E., Thomas, D. Y. & Whiteway, M. Cell cycle- and Cln2p–Cdc28p-dependent phosphorylation of the yeast Ste20p protein kinase. J. Biol. Chem. 273, 28107–28115 (1998).
Oda, Y., Huang, K., Cross, F. R., Cowburn, D. & Chait, B. T. Accurate quantitation of protein expression and site-specific phosphorylation. Proc. Natl Acad. Sci. USA 96, 6591–6596 (1999).
Lew, D. J. & Reed, S. I. A cell cycle checkpoint monitors cell morphogenesis in budding yeast. J. Cell Biol. 129, 739–749 (1995).
Sia, R. A., Herald, H. A. & Lew, D. J. Cdc28 tyrosine phosphorylation and the morphogenesis checkpoint in budding yeast. Mol. Biol. Cell 7, 1657–1666 (1996).
McNulty, J. J. & Lew, D. J. Swe1p responds to cytoskeletal perturbation, not bud size, in S. cerevisiae. Curr. Biol. 15, 2190–2198 (2005).
McMillan, J. N., Sia, R. A., Bardes, E. S. & Lew, D. J. Phosphorylation-independent inhibition of Cdc28p by the tyrosine kinase Swe1p in the morphogenesis checkpoint. Mol. Cell. Biol. 19, 5981–5990 (1999).
Waters, J. C., Chen, R. H., Murray, A. W. & Salmon, E. D. Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J. Cell Biol. 141, 1181–1191 (1998).
Chen, R. H., Brady, D. M., Smith, D., Murray, A. W. & Hardwick, K. G. The spindle checkpoint of budding yeast depends on a tight complex between the Mad1 and Mad2 proteins. Mol. Biol. Cell 10, 2607–2618 (1999).
Brady, D. M. & Hardwick, K. G. Complex formation between Mad1p, Bub1p and Bub3p is crucial for spindle checkpoint function. Curr. Biol. 10, 675–678 (2000).
Hwang, L. H. et al. Budding yeast Cdc20: a target of the spindle checkpoint. Science 279, 1041–1044 (1998).
Visintin, R. et al. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol. Cell 2, 709–718 (1998).
Bardin, A. J., Visintin, R. & Amon, A. A mechanism for coupling exit from mitosis to partitioning of the nucleus. Cell 102, 21–31 (2000).
Fraschini, R., Formenti, E., Lucchini, G. & Piatti, S. Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic checkpoint via a different pathway from Mad2. J. Cell Biol. 145, 979–991 (1999).
Alexandru, G., Zachariae, W., Schleiffer, A. & Nasmyth, K. Sister chromatid separation and chromosome re-duplication are regulated by different mechanisms in response to spindle damage. EMBO J. 18, 2707–2721 (1999).
Lew, D. J. & Reed, S. I. Morphogenesis in the yeast cell cycle: regulation by Cdc28 and cyclins. J. Cell Biol. 120, 1305–1320 (1993).
Benton, B. K., Tinkelenberg, A. H., Jean, D., Plump, S. D. & Cross, F. R. Genetic analysis of Cln–Cdc28 regulation of cell morphogenesis in budding yeast. EMBO J. 12, 5267–5275 (1993).
Cvrckova, F. & Nasmyth, K. Yeast G1 cyclins CLN1 and CLN2 and a GAP-like protein have a role in bud formation. EMBO J. 12, 5277–5286 (1993).
Chant, J. & Herskowitz, I. Genetic control of bud site selection in yeast by a set of gene products that constitute a morphogenetic pathway. Cell 65, 1203–1212 (1991).
Moffat, J. & Andrews, B. Late-G1 cyclin-CDK activity is essential for control of cell morphogenesis in budding yeast. Nature Cell Biol. 6, 59–66 (2004). Describes a Cln-specific role for budding and morphogenesis, but not other cell-cycle events such as DNA replication or SPB duplication.
Sreenivasan, A., Bishop, A. C., Shokat, K. M. & Kellogg, D. R. Specific inhibition of Elm1 kinase activity reveals functions required for early G1 events. Mol. Cell. Biol. 23, 6327–6337 (2003).
Altman, R. & Kellogg, D. Control of mitotic events by Nap1 and the Gin4 kinase. J. Cell Biol. 138, 119–130 (1997).
Kellogg, D. R., Kikuchi, A., Fujii-Nakata, T., Turck, C. W. & Murray, A. W. Members of the NAP/SET family of proteins interact specifically with B-type cyclins. J. Cell Biol. 130, 661–673 (1995).
Kellogg, D. R. & Murray, A. W. NAP1 acts with Clb1 to perform mitotic functions and to suppress polar bud growth in budding yeast. J. Cell Biol. 130, 675–685 (1995).
Mortensen, E. M., McDonald, H., Yates, J. 3rd & Kellogg, D. R. Cell cycle-dependent assembly of a Gin4–septin complex. Mol. Biol. Cell 13, 2091–2105 (2002).
Masumoto, H., Sugino, A. & Araki, H. Dpb11 controls the association between DNA polymerases α and ɛ and the autonomously replicating sequence region of budding yeast. Mol. Cell. Biol. 20, 2809–2817 (2000).
Masumoto, H., Muramatsu, S., Kamimura, Y. & Araki, H. S-Cdk-dependent phosphorylation of Sld2 essential for chromosomal DNA replication in budding yeast. Nature 415, 651–655 (2002). Describes the first identified essential substrate of Cdc28 that is targeted by S-phase Clb–Cdc2 complexes and the phosphorylation of which is required for progression through S phase.
Kesti, T., McDonald, W. H., Yates, J. R., 3rd & Wittenberg, C. Cell cycle-dependent phosphorylation of the DNA polymerase epsilon subunit, Dpb2, by the Cdc28 cyclin-dependent protein kinase. J. Biol. Chem. 279, 14245–14255 (2004).
Elsasser, S., Lou, F., Wang, B., Campbell, J. L. & Jong, A. Interaction between yeast Cdc6 protein and B-type cyclin/Cdc28 kinases. Mol. Biol. Cell 7, 1723–1735 (1996).
Drury, L. S., Perkins, G. & Diffley, J. F. The cyclin-dependent kinase Cdc28p regulates distinct modes of Cdc6p proteolysis during the budding yeast cell cycle. Curr. Biol. 10, 231–240 (2000).
Calzada, A., Sanchez, M., Sanchez, E. & Bueno, A. The stability of the Cdc6 protein is regulated by cyclin-dependent kinase/cyclin B complexes in Saccharomyces cerevisiae. J. Biol. Chem. 275, 9734–9741 (2000).
Mimura, S., Seki, T., Tanaka, S. & Diffley, J. F. Phosphorylation-dependent binding of mitotic cyclins to Cdc6 contributes to DNA replication control. Nature 431, 1118–1123 (2004).
Labib, K., Diffley, J. F. & Kearsey, S. E. G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nature Cell Biol. 1, 415–422 (1999).
Nguyen, V. Q., Co, C., Irie, K. & Li, J. J. Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins Mcm2–7. Curr. Biol. 10, 195–205 (2000).
Nguyen, V. Q., Co, C. & Li, J. J. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature 411, 1068–1073 (2001).
Wilmes, G. M. et al. Interaction of the S-phase cyclin Clb5 with an “RXL” docking sequence in the initiator protein Orc6 provides an origin-localized replication control switch. Genes Dev. 18, 981–991 (2004).
Archambault, V., Buchler, N. E., Wilmes, G. M., Jacobson, M. D. & Cross, F. R. Two-faced cyclins with eyes on the targets. Cell Cycle 4, 125–130 (2005).
Haase, S. B., Winey, M. & Reed, S. I. Multi-step control of spindle pole body duplication by cyclin-dependent kinase. Nature Cell Biol. 3, 38–42 (2001). Describes the functions of different cyclin–Cdc28 complexes in SPB duplication, maturation and separation.
Jaspersen, S. L. & Winey, M. The budding yeast spindle pole body: structure, duplication, and function. Annu. Rev. Cell. Dev. Biol. 20, 1–28 (2004).
Jaspersen, S. L. et al. Cdc28/Cdk1 regulates spindle pole body duplication through phosphorylation of Spc42 and Mps1. Dev. Cell 7, 263–274 (2004). Identifies substrates of Cln–Cdc28 complexes that promote SPB duplication.
Castillo, A. R., Meehl, J. B., Morgan, G., Schutz-Geschwender, A. & Winey, M. The yeast protein kinase Mps1p is required for assembly of the integral spindle pole body component Spc42p. J. Cell Biol. 156, 453–465 (2002).
Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859–864 (2003).
Segal, M., Clarke, D. J. & Reed, S. I. Clb5-associated kinase activity is required early in the spindle pathway for correct preanaphase nuclear positioning in Saccharomyces cerevisiae. J. Cell Biol. 143, 135–145 (1998).
Segal, M. et al. Coordinated spindle assembly and orientation requires Clb5p-dependent kinase in budding yeast. J. Cell Biol. 148, 441–452 (2000).
Pereira, G., Tanaka, T. U., Nasmyth, K. & Schiebel, E. Modes of spindle pole body inheritance and segregation of the Bfa1p–Bub2p checkpoint protein complex. EMBO J. 20, 6359–6370 (2001).
Miller, R. K. & Rose, M. D. Kar9p is a novel cortical protein required for cytoplasmic microtubule orientation in yeast. J. Cell Biol. 140, 377–390 (1998).
Miller, R. K., Matheos, D. & Rose, M. D. The cortical localization of the microtubule orientation protein, Kar9p, is dependent upon actin and proteins required for polarization. J. Cell Biol. 144, 963–975 (1999).
Maekawa, H., Usui, T., Knop, M. & Schiebel, E. Yeast Cdk1 translocates to the plus end of cytoplasmic microtubules to regulate bud cortex interactions. EMBO J. 22, 438–449 (2003).
Liakopoulos, D., Kusch, J., Grava, S., Vogel, J. & Barral, Y. Asymmetric loading of Kar9 onto spindle poles and microtubules ensures proper spindle alignment. Cell 112, 561–574 (2003). Identifies a Clb4-specific role for orienting the mitotic spindle.
Maekawa, H. & Schiebel, E. Cdk1–Clb4 controls the interaction of astral microtubule plus ends with subdomains of the daughter cell cortex. Genes Dev. 18, 1709–1724 (2004).
Moore, J. K., D'Silva, S. & Miller, R. K. The CLIP-170 homologue Bik1p promotes the phosphorylation and asymmetric localization of Kar9p. Mol. Biol. Cell 17, 178–191 (2006).
Grava, S., Schaerer, F., Faty, M., Philippsen, P. & Barral, Y. Asymmetric recruitment of dynein to spindle poles and microtubules promotes proper spindle orientation in yeast. Dev. Cell 10, 425–439 (2006).
Schwab, M., Lutum, A. S. & Seufert, W. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis. Cell 90, 683–693 (1997).
Jaspersen, S. L., Charles, J. F., Tinker-Kulberg, R. L. & Morgan, D. O. A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae. Mol. Biol. Cell 9, 2803–2817 (1998).
Sullivan, M. & Uhlmann, F. A non-proteolytic function of separase links the onset of anaphase to mitotic exit. Nature Cell Biol. 5, 249–254 (2003).
Lew, D. J. & Burke, D. J. The spindle assembly and spindle position checkpoints. Annu. Rev. Genet. 37, 251–282 (2003).
Jaspersen, S. L. & Morgan, D. O. Cdc14 activates Cdc15 to promote mitotic exit in budding yeast. Curr. Biol. 10, 615–618 (2000).
Stegmeier, F., Visintin, R. & Amon, A. Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase. Cell 108, 207–220 (2002).
Azzam, R. et al. Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. Science 305, 516–519 (2004).
Queralt, E., Lehane, C., Novak, B. & Uhlmann, F. Downregulation of PP2ACdc55 phosphatase by separase initiates mitotic exit in budding yeast. Cell 125, 719–732 (2006).
Shou, W. et al. Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit. Mol. Cell 8, 45–55 (2001).
Nasmyth, K. Evolution of the cell cycle. Philos. Trans. R Soc. Lond. B Biol. Sci. 349, 271–281 (1995).
Stern, B. & Nurse, P. A quantitative model for the Cdc2 control of S phase and mitosis in fission yeast. Trends Genet. 12, 345–350 (1996).
Acknowledgements
J.B. is supported by a postdoctoral fellowship from the American Cancer Society. F.R.C. is supported by the National Institutes of Health.
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Glossary
- Spindle pole body
-
(SPB). The yeast equivalent of the centrosome, which nucleates microtubules, including those that will form the spindle.
- Anaphase promoting complex
-
(APC). A multicomponent ubiquitin ligase that targets proteins for degradation by the proteasome.
- Forkhead transcription factor
-
A member of a protein family that consists of more than 40 members. This family belongs to the winged-helix class of DNA-binding proteins and its members are involved in diverse cellular functions, including glucose metabolism, apoptosis and cell-cycle regulation.
- 26S proteasome
-
A large multisubunit protease complex that selectively degrades intracellular proteins. Targeting to proteasomes occurs through the attachment of polyubiquitin tags.
- SCF complex
-
A multisubunit ubiquitin ligase that contains Skp1, a member of the cullin family (Cdc53) and an F-box protein, as well as a RING-finger-containing protein (Roc1; also known as Rbx1).
- F-box protein
-
A component of the machinery for the ubiquitin-dependent degradation of proteins. F-box proteins recognize specific substrates and, with the help of other subunits of the E3 ubiquitin ligase, deliver them to the E2 ubiquitin-conjugating enzyme.
- α-factor
-
A peptide that is secreted by yeast cells of the α-mating type that causes cells of the a-mating type to prepare for mating by inducing arrest in G1, morphological changes and the transcription of genes involved in mating.
- Spindle-assembly checkpoint
-
A checkpoint that monitors the correct attachment of chromosomes to spindles in the metaphase–anaphase transition. Activation of this checkpoint causes cell-cycle arrest as a result of the inhibition of the anaphase-promoting complex (APC).
- Kinetochore
-
A multiprotein complex that assembles on centromeric DNA and mediates the attachment and movement of chromosomes along the microtubules of the mitotic spindle.
- Mitotic exit network
-
(MEN). A signal-transduction pathway that is required for sustained Cdc14 release during anaphase. This allows for the degradation of mitotic cyclins and the accumulation of the Clb–Cdc28 inhibitor Sic1.
- Bfa1–Bub2 GTPase-activating complex
-
A complex that localizes to spindle pole bodies and inhibits the activation of the mitotic exit network until the mitotic spindle is properly aligned along the mother–bud axis.
- Septin ring
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A complex of seven septin proteins that forms a ring at the incipient bud site before bud emergence. The septin ring determines bud-site selection and serves as a scaffold for proteins, including those involved in cell polarity, cell-wall synthesis and cytokinesis.
- Origin recognition complex
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(ORC). A six-subunit complex that associates with replication origins throughout the cell cycle and recruits additional replication factors to initiate DNA replication.
- Minichromosome maintenance (Mcm) proteins
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Six minichromosome maintenance (Mcm) proteins form a complex that binds DNA at origins of replication and helps unwind DNA to initiate replication.
- RXL motif
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A protein sequence in Cdc28 substrates that mediates the interaction with the hydrophobic patch of cyclins.
- Cdc14 early anaphase release (FEAR) network
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A signal-transduction pathway that promotes the transient release of Cdc14 from the nucleolus during early anaphase. This allows for stabilization of the mitotic spindle, segregation of ribosomal DNA and activation of the mitotic exit network.
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Bloom, J., Cross, F. Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol 8, 149–160 (2007). https://doi.org/10.1038/nrm2105
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DOI: https://doi.org/10.1038/nrm2105
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