Interplay Between Cell Growth And Cell Cycle In Plants

The growth of organs and whole plants depends on both cell growth and cell-cycle progression, but the interaction between both processes is poorly understood. In plants, the balance between growth and cell-cycle progression requires coordinated regulation of four different processes: macromolecular synthesis (cytoplasmic growth), turgor-driven cell-wall extension, mitotic cycle, and endocycle. Potential feedbacks between these processes include a cell-size checkpoint operating before DNA synthesis and a link between DNA contents and maximum cell size. In addition, key intercellular signals and growth regulatory genes appear to target at the same time cell-cycle and cell-growth functions. For example, auxin, gibberellin, and brassinosteroid all have parallel links to cell-cycle progression (through S-phase Cyclin D-CDK and the anaphase-promoting complex) and cell-wall functions (through cell-wall extensibility or microtubule dynamics). Another intercellular signal mediated by microtubule dynamics is the mechanical stress caused by growth of interconnected cells. Superimposed on developmental controls, sugar signalling through the TOR pathway has recently emerged as a central control point linking cytoplasmic growth, cell-cycle and cell-wall functions. Recent progress in quantitative imaging and computational modelling will facilitate analysis of the multiple interconnections between plant cell growth and cell cycle and ultimately will be required for the predictive manipulation of plant growth. © The Author 2013.651027032714Achard, P., Gusti, A., Cheminant, S., Alioua, M., Dhondt, S., Coppens, F., Beemster, G.T.S., Genschik, P., Gibberellin signaling controls cell proliferation rate in Arabidopsis (2009) Current Biology, 19, pp. 1188-1193Adachi, S., Minamisawa, K., Okushima, Y., Programmed induction of endoreduplication by DNA double-strand breaks in Arabidopsis (2011) Proceedings of the National Academy of Sciences USA, 108, pp. 10004-10009Andriankaja, M., Dhondt, S., De Bodt, S., Exit from proliferation during leaf development in Arabidopsis thaliana: A not-sogradual process (2012) Developmental Cell, 22, pp. 64-78Baumgartner, S., Tolic-Norrelykke, I.M., Growth pattern of single fission yeast cells Is bilinear and depends on temperature and DNA synthesis (2009) Biophysical Journal, 96, pp. 4336-4347Berkowitz, O., Jost, R., Pollmann, S., Masle, J., Characterization of TCTP, the translationally controlled tumor protein, from Arabidopsis thaliana (2008) The Plant Cell, 20, pp. 3430-3447Breuninger, H., Lenhard, M., Control of tissue and organ growth in plants (2010) Current Topics in Developmental Biology, 91, pp. 185-220. , In: CPT Marja, ed. Waltham, MA Academic PressBrioudes, F., Thierry, A.-M., Chambrier, P., Mollereau, B., Bendahmane, M., Translationally controlled tumor protein is a conserved mitotic growth integrator in animals and plants (2010) Proceedings of the National Academy of Sciences USA, 107, pp. 16384-16389Caesar, K., Elgass, K., Chen, Z., Huppenberger, P., Witthöft, J., Schleifenbaum, F., Blatt, M.R., Harter, K., A fast brassinolide-regulated response pathway in the plasma membrane of Arabidopsis thaliana (2011) The Plant Journal, 66, pp. 528-540Caldana, C., Li, Y., Leisse, A., Zhang, Y., Bartholomaeus, L., Fernie, A.R., Willmitzer, L., Giavalisco, P., Systemic analysis of inducible target of rapamycin mutants reveal a general metabolic switch controlling growth in Arabidopsis thaliana (2013) The Plant Journal, 73, pp. 897-909Churchman, M.L., Brown, M.L., Kato, N., Kirik, V., Hulskamp, M., Inze, D., De Veylder, L., Larkin, J.C., SIAMESE, a plant-specific cell cycle regulator, controls endoreplication onset in Arabidopsis thaliana (2006) Plant Cell, 18 (11), pp. 3145-3157. , DOI 10.1105/tpc.106.044834Claeys, H., Skirycz, A., Maleux, K., Inze, D., DELLA signaling mediates stress-induced cell differentiation in Arabidopsis leaves through modulation of anaphase-promoting complex cyclosome activity (2012) Plant Physiology, 159, pp. 739-747Clouse, S.D., Brassinosteroid signal transduction: From receptor kinase activation to transcriptional networks regulating plant development (2011) The Plant Cell, 23, pp. 1219-1230Conlon, I., Raff, M., Differences in the way a mammalian cell and yeast cells coordinate cell growth and cell-cycle progression (2003) Journal of Biology, 2, p. 7Coudreuse, D., Nurse, P., Driving the cell cycle with a minimal CDK control network (2010) Nature, 468, pp. 1074-1079Danisman, S., Van Der Wal, F., Dhondt, S., Arabidopsis class i and class II TCP transcription factors regulate jasmonic acid metabolism and leaf development antagonistically (2012) Plant Physiology, 159, pp. 1511-1523De Schutter, K., Joubes, J., Cools, T., Verkest, A., Corellou, F., Babiychuk, E., Van Der Schueren, E., De Veylder, L., Arabidopsis WEE1 kinase controls cell cycle arrest in response to activation of the DNA integrity checkpoint (2007) Plant Cell, 19 (1), pp. 211-225. , DOI 10.1105/tpc.106.045047De Veylder, L., Beeckman, T., Inze, D., The ins and outs of the plant cell cycle (2007) Nature Reviews Molecular Cell Biology, 8 (8), pp. 655-665. , DOI 10.1038/nrm2227, PII NRM2227Deprost, D., Yao, L., Sormani, R., Moreau, M., Leterreux, G., Bedu, M., Robaglia, C., Meyer, C., The Arabidopsis TOR kinase links plant growth, yield, stress resistance and mRNA translation (2007) EMBO Reports, 8 (9), pp. 864-870. , DOI 10.1038/sj.embor.7401043, PII 7401043Dewitte, W., Murray, J.A.H., The plant cell cycle (2003) Annual Review of Plant Biology, 54, pp. 235-264. , DOI 10.1146/annurev.arplant.54.031902.134836Dewitte, W., Riou-Khamlichi, C., Scofield, S., Healy, J.M.S., Jacqmard, A., Kilby, N.J., Murray, J.A.H., Altered cell cycle distribution, hyperplasia, and inhibited differentiation in arabidopsis caused by the D-Type cyclin CYCD3 (2003) Plant Cell, 15 (1), pp. 79-92. , DOI 10.1105/tpc.004838Dewitte, W., Scofield, S., Alcasabas, A.A., Maughan, S.C., Menges, M., Braun, N., Collins, C., Murray, J.A.H., Arabidopsis CYCD3 D-Type cyclins link cell proliferation and endocycles and are rate-limiting for cytokinin responses (2007) Proceedings of the National Academy of Sciences of the United States of America, 104 (36), pp. 14537-14542. , http://www.pnas.org/cgi/reprint/104/36/14537, DOI 10.1073/pnas.0704166104Dissmeyer, N., Weimer, A.K., Pusch, S., Control of cell proliferation, organ growth, and DNA damage response operate independently of dephosphorylation of the Arabidopsis Cdk1 homolog CDKA;1 (2009) The Plant Cell, 21, pp. 3641-3654Donnelly, P.M., Bonetta, D., Tsukaya, H., Dengler, R.E., Dengler, N.G., Cell cycling and cell enlargement in developing leaves of Arabidopsis (1999) Developmental Biology, 215, pp. 407-419Doonan, J.H., Sablowski, R., Walls around tumours-why plants do not develop cancer (2010) Nature Reviews Cancer, 10, pp. 794-802Dornelas, M.C., Patreze, C.M., Angenent, G.C., Immink, R.G.H., MADS: The missing link between identity and growth? (2011) Trends in Plant Science, 16, pp. 89-97Dowling, R.J.O., Topisirovic, I., Alain, T., Mtorc1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs (2010) Science, 328, pp. 1172-1176Efroni, I., Blum, E., Goldshmidt, A., Eshed, Y., A protracted and dynamic maturation schedule underlies Arabidopsis leaf development (2008) Plant Cell, 20 (9), pp. 2293-2306. , http://www.plantcell.org/cgi/reprint/20/9/2293, DOI 10.1105/tpc.107.057521Elsner, J., Michalski, M., Kwiatkowska, D., Spatiotemporal variation of leaf epidermal cell growth: A quantitative analysis of Arabidopsis thaliana wild-Type and triple cyclinD3 mutant plants (2012) Annals of Botany, 109, pp. 897-910Ferjani, A., Horiguchi, G., Yano, S., Tsukaya, H., Analysis of leaf development in fugu mutants of Arabidopsis reveals three compensation modes that modulate cell expansion in determinate organs (2007) Plant Physiology, 144 (2), pp. 988-999. , http://www.plantphysiol.org/cgi/reprint/144/2/988.pdf, DOI 10.1104/pp.107.099325Ferjani, A., Segami, S., Horiguchi, G., Muto, Y., Maeshima, M., Tsukaya, H., Keep an eye on PPi: The vacuolar-Type H+-pyrophosphatase regulates postgerminative development in Arabidopsis (2011) The Plant Cell, 23, pp. 2895-2908Fernandez, R., Das, P., Mirabet, V., Moscardi, E., Traas, J., Verdeil, J.-L., Malandain, G., Godin, C., Imaging plant growth in 4D: Robust tissue reconstruction and lineaging at cell resolution (2010) Nature Methods, 7, pp. 547-553Fujikura, U., Horiguchi, G., Ponce, M.R., Micol, J.L., Tsukaya, H., Coordination of cell proliferation and cell expansion mediated by ribosome-related processes in the leaves of Arabidopsis thaliana (2009) The Plant Journal, 59, pp. 499-508Gaudin, V., Lunness, P.A., Fobert, P.R., Towers, M., Riou-Khamlichi, C., Murray, J.A.H., Coen, E., Doonan, J.H., The expression of D-cyclin genes defines distinct developmental zones in snapdragon apical meristems and is locally regulated by the Cycloidea gene (2000) Plant Physiology, 122 (4), pp. 1137-1148Gonzalez-Garcia, M.-P., Vilarrasa-Blasi, J., Zhiponova, M., Divol, F., Mora-Garcia, S., Russinova, E., Cano-Delgado, A.I., Brassinosteroids control meristem size by promoting cell cycle progression in Arabidopsis roots (2011) Development, 138, pp. 849-859Goranov, A.I., Amon, A., Growth and division, not a one-way road (2010) Current Opinion in Cell Biology, 22, pp. 795-800Grandjean, O., Vernoux, T., Laufs, P., Belcram, K., Mizukami, Y., Traas, J., In vivo analysis of cell division, cell growth, and differentiation at the shoot apical meristem in Arabidopsis (2004) The Plant Cell, 16, pp. 74-87Guo, S., Xu, Y., Liu, H., Mao, Z., Zhang, C., Ma, Y., Zhang, Q., Chong, K., The interaction between OsMADS57 and OsTB1 modulates rice tillering via DWARF14 (2013) Nature Communications, 4, p. 1566Gutzat, R., Borghi, L., Gruissem, W., Emerging roles of RETINOBLASTOMA-RELATED proteins in evolution and plant development (2012) Trends in Plant Science, 17, pp. 139-148Halder, G., Johnson, R.L., Hippo signaling: Growth control and beyond (2011) Development, 138, pp. 9-22Hamant, O., Heisler, M., Jonsson, H., Developmental patterning by mechanical signals in Arabidopsis (2008) Science, 322, pp. 1650-1655Hemerly, A., Engler Jd, A., Bergounioux, C., Van Montagu, M., Engler, G., Inze, D., Ferreira, P., Dominant negative mutants of the Cdc2 kinase uncouple cell division from iterative plant development (1995) EMBO Journal, 14, pp. 3925-3936Herve, C., Dabos, P., Bardet, C., Jauneau, A., Auriac, M.C., Ramboer, A., Lacout, F., Tremousaygue, D., In vivo interference with AtTCP20 function induces severe plant growth alterations and deregulates the expression of many genes important for development (2009) Plant Physiology, 149, pp. 1462-1477Hisanaga, T., Ali, F., Horiguchi, G., ATM-dependent DNA damage response acts as an upstream trigger for compensation in fas1 mutation during Arabidopsis leaf development (2013) Plant Physiology, 162, pp. 831-841Horiguchi, G., Tsukaya, H., Organ size regulation in plants: Insights from compensation (2011) Frontiers in Plant Science, 2, p. 24John, P.C.L., Qi, R., Cell division and endoreduplication: Doubtful engines of vegetative growth (2008) Trends in Plant Science, 13, pp. 121-127Jorgensen, P., Tyers, M., How cells coordinate growth and division (2004) Current Biology, 14 (23), pp. R1014-R1027. , DOI 10.1016/j.cub.2004.11.027, PII S0960982204008954Kaufmann, K., Muiño, J.M., Jauregui, R., Airoldi, C.A., Smaczniak, C., Krajewski, P., Angenent, G.C., Target genes of the MADS transcription factor SEPALLATA3: Integration of developmental and hormonal pathways in the Arabidopsis flower (2009) PLoS Biology, 7, pp. e90Kawade, K., Horiguchi, G., Tsukaya, H., Non-cell-Autonomously coordinated organ size regulation in leaf development (2010) Development, 137, pp. 4221-4227Kazama, T., Ichihashi, Y., Murata, S., Tsukaya, H., The mechanism of cell cycle arrest front progression explained by a KLUH CYP78A5-dependent mobile growth factor in developing leaves of Arabidopsis thaliana (2010) Plant and Cell Physiology, 51, pp. 1046-1054Krizek, B.A., Ectopic expression of AINTEGUMENTA in Arabidopsis plants results in increased growth of floral organs (1999) Developmental Genetics, 25 (3), pp. 224-236. , DOI 10.1002/(SICI)1520-6408(1999)25:33.0.CO;2-YLammens, T., Boudolf, V.R., Kheibarshekan, L., Atypical E2F activity restrains APC CCCS52A2 function obligatory for endocycle onset (2008) Proceedings of the National Academy of Sciences, USA, 105, pp. 14721-14726Laskowski, M., Grieneisen, V., Hofhuis, H., Ten Hove, C., Hogeweg, P., Maree, A., Scheres, B., Root system architecture from coupling cell shape to auxin transport (2008) PLoS Biology, 6, pp. e307Denchi, E.L., Celli, G., De Lange, T., Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication (2006) Genes and Development, 20 (19), pp. 2648-2653. , http://www.genesdev.org/cgi/reprint/20/19/2648, DOI 10.1101/gad.1453606Lecuit, T., Le Goff, L., Orchestrating size and shape during morphogenesis (2007) Nature, 450 (7167), pp. 189-192. , DOI 10.1038/nature06304, PII NATURE06304Lee, H.O., Davidson, J.M., Duronio, R.J., Endoreplication: Polyploidy with purpose (2009) Genes and Development, 23, pp. 2461-2477Locascio, A., Blazquez, M.A., Alabadi, D., Dynamic regulation of cortical microtubule organization through prefoldin-DELLA interaction (2013) Current Biology, 23, pp. 804-809Maines, J.Z., Stevens, L.M., Tong, X., Stein, D., Drosophila dMyc is required for ovary cell growth and endoreplication (2004) Development, 131 (4), pp. 775-786. , DOI 10.1242/dev.00932Martín-Trillo, M., Cubas, P., TCP genes: A family snapshot ten years later (2010) Trends in Plant Science, 15, pp. 31-39Menand, B., Desnos, T., Nussaume, L., Berger, F., Bouchez, D., Meyer, C., Robaglia, C., Expression and disruption of the Arabidopsis TOR (target of rapamycin) gene (2002) Proceedings of the National Academy of Sciences, USA, 99, pp. 6422-6427Mizukami, Y., Fischer, R.L., Plant organ size control: AINTEGUMENTA regulates growth and cell numbers during organogenesis (2000) Proceedings of the National Academy of Sciences of the United States of America, 97 (2), pp. 942-947. , DOI 10.1073/pnas.97.2.942Moseley, J.B., Mayeux, A., Paoletti, A., Nurse, P., A spatial gradient coordinates cell size and mitotic entry in fission yeast (2009) Nature, 459, pp. 857-860Nath, U., Crawford, B.C.W., Carpenter, R., Coen, E., Genetic control of surface curvature (2003) Science, 299 (5611), pp. 1404-1407. , DOI 10.1126/science.1079354Neto-Silva, R.M., Wells, B.S., Johnston, L.A., Mechanisms of growth and homeostasis in the Drosophila wing (2009) Annual Review of Cell and Developmental Biology, 25, pp. 197-220O'Farrell, P.H., Triggering the all-or-nothing switch into mitosis (2001) Trends in Cell Biology, 11 (12), pp. 512-519. , DOI 10.1016/S0962-8924(01)02142-0, PII S0962892401021420Paredez, A.R., Somerville, C.R., Ehrhardt, D.W., Visualization of cellulose synthase demonstrates functional association with microtubules (2006) Science, 312 (5779), pp. 1491-1495. , DOI 10.1126/science.1126551Peaucelle, A., Braybrook, S.A., Le Guillou, L., Bron, E., Kuhlemeier, C., Höfte, H., Pectin-induced changes in cell wall mechanics underlie organ initiation in Arabidopsis (2011) Current Biology, 21, pp. 1720-1726Peaucelle, A., Louvet, R., Johansen, J.N., Hofte, H., Laufs, P., Pelloux, J., Mouille, G., Arabidopsis phyllotaxis is controlled by the methyl-esterification status of cell-wall pectins (2008) Current Biology, 18, p. 1943Peret, B., Li, G., Zhao, J., Auxin regulates aquaporin function to facilitate lateral root emergence (2012) Nature Cell Biology, 14, pp. 991-998Perrot-Rechenmann, C., Cellular responses to auxin: Division versus expansion (2010) Cold Spring Harbor Perspectives in Biology, 2, pp. a001446Pien, S., Wyrzykowska, J., McQueen-Mason, S., Smart, C., Fleming, A., Local expression of expansin induces the entire process of leaf development and modifies leaf shape (2001) Proceedings of the National Academy of Sciences of the United States of America, 98 (20), pp. 11812-11817. , DOI 10.1073/pnas.191380498Qi, R., John, P.C.L., Expression of genomic AtCYCD2;1 in arabidopsis induces cell division at smaller cell sizes: Implications for the control of plant growth (2007) Plant Physiology, 144 (3), pp. 1587-1597. , http://www.plantphysiol.org/cgi/reprint/144/3/1587.pdf, DOI 10.1104/pp.107.096834Riou-Khamlichi, C., Huntley, R., Jacqmard, A., Murray, J.A., Cytokinin activation of Arabidopsis cell division through a D-Type cyclin (1999) Science, 283, pp. 1541-1544Riou-Khamlichi, C., Menges, M., Healy, J.M.S., Murray, J.A.H., Sugar control of the plant cell cycle: Differential regulation of Arabidopsis D-Type cyclin gene expression (2000) Molecular and Cellular Biology, 20 (13), pp. 4513-4521. , DOI 10.1128/MCB.20.13.4513-4521.2000Rodriguez, R.E., Mecchia, M.A., Debernardi, J.M., Schommer, C., Weigel, D., Palatnik, J.F., Control of cell proliferation in Arabidopsis thaliana by microRNA miR396 (2010) Development, 137, pp. 103-112Roeder, A.H.K., When and where plant cells divide: A perspective from computational modeling (2012) Current Opinion in Plant Biology, 15, pp. 638-644Roeder, A.H.K., Chickarmane, V., Cunha, A., Obara, B., Manjunath, B.S., Meyerowitz, E.M., Variability in the control of cell division underlies sepal epidermal patterning in Arabidopsis thaliana (2010) PLoS Biology, 8, pp. e1000367Roeder, A.H.K., Tarr, P.T., Tobin, C., Zhang, X., Chickarmane, V., Cunha, A., Meyerowitz, E.M., Computational morphodynamics of plants: Integrating development over space and time (2011) Nature Reviews Molecular Cell Biology, 12, pp. 265-273Sanz, L., Dewitte, W., Forzani, C., The Arabidopsis D-Type cyclin CYCD2;1 and the inhibitor ICK2 KRP2 modulate auxin-induced lateral root formation (2011) The Plant Cell, 23, pp. 641-660Sauret-Güeto, S., Schiessl, K., Bangham, A., Sablowski, R., Coen, E., JAGGED controls Arabidopsis petal growth and shape by interacting with a divergent polarity field (2013) PLoS Biology, 11, pp. e1001550Schiessl, K., Kausika, S., Southam, P., Bush, M., Sablowski, R., JAGGED controls growth anisotropy and coordination between cell size and cell cycle during plant organogenesis (2012) Current Biology, 22, pp. 1739-1746Schommer, C., Palatnik, J.F., Aggarwal, P., Chételat, A., Cubas, P., Farmer, E.E., Nath, U., Weigel, D., Control of jasmonate biosynthesis and senescence by miR319 targets (2008) PLoS Biology, 6, pp. e230Shani, E., Weinstain, R., Zhang, Y., Castillejo, C., Kaiserli, E., Chory, J., Tsien, R.Y., Estelle, M., Gibberellins accumulate in the elongating endodermal cells of Arabidopsis root (2013) Proceedings of the National Academy of Sciences USA, 110, pp. 4834-4839Su, T.T., O'Farrell, P.H., Size control: Cell proliferation does not equal growth (1998) Current Biology, 8 (19), pp. R687-R689Sugimoto-Shirasu, K., Roberts, K., Big it up': Endoreduplication and cell-size control in plants (2003) Current Opinion in Plant Biology, 6, p. 544Talia, S.D., Skotheim, J.M., Bean, J.M., Siggia, E.D., Cross, F.R., The effects of molecular noise and size control on variability in the budding yeast cell cycle (2007) Nature, 448 (7156), pp. 947-951. , DOI 10.1038/nature06072, PII NATURE06072Tzur, A., Kafri, R., Lebleu, V.S., Lahav, G., Kirschner, M.W., Cell growth and size homeostasis in proliferating animal cells (2009) Science, 325, pp. 167-171Uyttewaal, M., Burian, A., Alim, K., Mechanical stress acts via katanin to amplify differences in growth rate between adjacent cells in Arabidopsis (2012) Cell, 149, pp. 439-451Uyttewaal, M., Traas, J., Hamant, O., Integrating physical stress, growth, and development (2010) Current Opinion in Plant Biology, 13, pp. 46-52Vanneste, S., Friml, J., Auxin: A trigger for change in plant development (2009) Cell, 136, pp. 1005-1016Verkest, A., Manes, C.-L., Vercruysse, S., Maes, S., Van Der Schueren, E., Beeckman, T., Genschik, P., De Veylder, L., The cyclin-dependent kinase inhibitor KRP2 controls the onset of the endoreduplication cycle during Arabidopsis leaf development through inhibition of mitotic CDKA;1 kinase complexes (2005) The Plant Cell, 17, pp. 1723-1736Verkest, A., Weinl, C., Inze, D., De Veylder, L., Schnittger, A., Switching the cell cycle. Kip-related proteins in plant cell cycle control (2005) Plant Physiology, 139, pp. 1099-1106Vlieghe, K., Boudolf, V., Beemster, G.T.S., Maes, S., Magyar, Z., Atanassova, A., De Almeida Engler, J., De Veylder, L., The DP-E2F-like gene DEL1 controls the endocycle in Arabidopsis thaliana (2005) Current Biology, 15 (1), pp. 59-63. , DOI 10.1016/j.cub.2004.12.038, PII S0960982204009972Wartlick, O., González-Gaitán, M., The missing link: Implementation of morphogenetic growth control on the cellular and molecular level (2011) Current Opinion in Genetics and Development, 21, pp. 690-695Wolf, S., Hématy, K., Höfte, H., Growth control and cell wall signaling in plants (2012) Annual Review of Plant Biology, 63, pp. 381-407Wu, C.-Y., Rolfe, P.A., Gifford, D.K., Fink, G.R., Control of transcription by cell size (2010) PLoS Biology, 8, pp. e1000523Wuest, S.E., Ó'Maoiléidigh, D.S., Rae, L., Kwasniewska, K., Raganelli, A., Hanczaryk, K., Lohan, A.J., Wellmer, F., Molecular basis for the specification of floral organs by APETALA3 and PISTILLATA (2012) Proceedings of the National Academy of Sciences USA, 109, pp. 13452-13457Wullschleger, S., Loewith, R., Hall, M.N., TOR signaling in growth and metabolism (2006) Cell, 124, pp. 471-484Xiong, Y., McCormack, M., Li, L., Hall, Q., Xiang, C., Sheen, J., Glucose-TOR signalling reprograms the transcriptome and activates meristems (2013) Nature, 496, pp. 181-186Zhao, X.A., Harashima, H., Dissmeyer, N., A general G1 S-phase cell-cyc