The Signal Transduction Pathway Upstream of CDC25 — ras — Adenylate Cyclase in the Yeast Saccharomyces Cerevisiae and its Relationship to Nutrient Control of Cell Cycle Progression

  • Johan M. Thevelein
  • Linda Van Aelst
  • Peter Durnez
  • Stefan Hohmann
Part of the NATO ASI Series book series (NSSA, volume 220)


In recent years several groups have made great efforts to unravel the function of the R A S genes in yeast in the hope of providing a model which could lead to a better understanding of the physiological role of mammalian ras genes and their oncogenic alleles. This research has led to two crucial breakthroughs: 1. The RAS proteins in yeast regulate adenylate cyclase activity in a way similar to the GS proteins of mammalian adenylate cyclase (Gibbs and Marshall, 1989) and 2. cAMP and hence also the RAS proteins, are involved in the control of progression over the ‘start’ (or decision) point in the G1 phase of the yeast cell cycle (Gibbs and Marshall, 1989). Particularly striking findings were that strains with yeast homologues of mammalian ras oncogenes and strains with elevated cAMP levels or elevated activity of cAMP-dependent protein kinase were unable to arrest at the ‘start’ point of the cell cycle under conditions of nutrient deprivation (Toda et al., 1985; Sass et al., 1986). Under these conditions wild type yeast cells arrest at ‘start’ and subsequently enter a resting state called GO (Pringle and Hartwell, 1981). On the other hand, strains with temperature-sensitive mutations in RAS or adenylate cyclase arrested at ‘start’ when shifted to the restrictive temperature (Matsumoto et al., 1985; De Vendittis et al., 1986).


Saccharomyces Cerevisiae Adenylate Cyclase cAMP Level Fermentable Sugar Glucose Repression 
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  1. Argüelles, J. C., Mbonyi, K., Van Aelst, L., Vanhalewyn, M., Jans, A. W. H., and Thevelein, J. M., 1990, Absence of glucose-induced cAMP signaling in the Saccharomyces cerevisiae mutants cat1 and cat3 which are deficient in derepression of glucose-repressible proteins, Arch. Microbiol., 154: 199.PubMedCrossRefGoogle Scholar
  2. Bedard, D. P., Johnston, G. C., and Singer, R. A., 1981, New mutations in the yeast Saccharomyces cerevisiae affecting completion of ‘Start’, Curr. Genet., 4: 205.CrossRefGoogle Scholar
  3. Beullens, M., Mbonyi, K., Geerts, L., Gladines, D., Detremerie, K., Jans, A. W. H., and Thevelein, J. M., 1988, Studies on the mechanism of the glucose-induced cAMP-signal in glycolysis- and glucose repression-mutants of the yeast Saccharomyces cerevisiae, Eur. J. Biochem., 172:227.PubMedCrossRefGoogle Scholar
  4. Bissinger, P. H., Wieser, R., Hamilton, B. and Ruis, H., 1989, Control of Saccharomyces cerevisiae catalase T gene (CTT1) expression by nutrient supply via the RAS-cyclic AMP pathway, Mol. Cell. Biol., 9: 1309.PubMedGoogle Scholar
  5. Bisson, L. F., Neigeborn, L., Carlson, M., and Fraenkel, D. G., 1987, The SNF3 gene is required for high-affinity glucose transport in Saccharomyces cerevisiae, J. Bacteriol., 169: 1656.PubMedGoogle Scholar
  6. Boorstein, W. R., and Craig, E. A., 1990, Regulation of a yeast HSP70 gene by a cAMP responsive transcriptional control element, EMBO J., 9: 2543.PubMedGoogle Scholar
  7. Broach, J. R., 1991, RAS genes in Saccharomyces cerevisiae: signal transduction in search of a pathway, Trends Genet., 7: 28.PubMedCrossRefGoogle Scholar
  8. Brenner, C, Nakayama N., Goebl, M., Tanaka, K., Toh-e, A., and Matsumoto, K., 1988, CDC33 encodes mRNA Cap-Binding Protein eIF-4E of Saccharomyces cerevisiae, Mol. Cell. Biol, 8: 3556.PubMedGoogle Scholar
  9. Camonis, J. H., Kalékine, M., Gondré, B., Garreau, H., Boy-Marcotte, E., and Jacquet, M., 1986, Characterization, cloning and sequence analysis of the CDC25 gene which controls the cyclic AMP level of Saccharomyces cerevisiae, EMBO J., 5: 375.PubMedGoogle Scholar
  10. Caspani, G., Tortora, P., Hanozet, G. M., and Guerritore, A., 1985, Glucose-stimulated cAMP increase may be mediated by intracellular acidification in Saccharomyces cerevisiae, FEBS Lett., 186: 75.CrossRefGoogle Scholar
  11. Cherry, J. R., Johnson, T. R., Dollard, C., Shuster, J. R., and Denis, C. L., 1989, Cyclic AMP-dependent protein kinase phosphorylates and inactivates the yeast transcriptional activator ADR1, Cell, 56: 409.PubMedCrossRefGoogle Scholar
  12. D’Amore, T., and Stewart, G. G., 1987, Ethanol tolerance of yeast, Enzyme Microb. Technol., 9: 322.CrossRefGoogle Scholar
  13. De Vendittis, E., Vitelli, A., Zahn, R., & Fasano, O., 1986, Suppression of defective RASI and RAS2 functions in yeast by an adenylate cyclase activated by a single aminoacid change, EMBO J., 5: 3657.PubMedGoogle Scholar
  14. Dumont, J. E., Jauniaux, J. C., and Roger, P. P., 1989, The cyclic AMP-mediated stimulation of cell proliferation, Trends Bloch. Sci., 14:67.CrossRefGoogle Scholar
  15. Entian, K. D., 1986, Glucose repression: a complex regulatory system in yeast, Microbiol. Sci., 3: 366.PubMedGoogle Scholar
  16. Eraso, P., Mazon, M. J., and Gancedo, J. M., 1987, Internal acidification and cAMP increase are not correlated in Saccharomyces cerevisiae, Eur. J. Biochem., 165: 671.PubMedCrossRefGoogle Scholar
  17. Fedor-Chaiken, M., Deschenes, R. J., and Broach, J. R., 1990, SRV2, a gene required for RAS activation of adenylate cyclase in yeast, Cell, 61: 329.PubMedCrossRefGoogle Scholar
  18. Field, J., Vojtek, A., Ballester, R., Bolger, G., Colicelli, J., Ferguson, K., Gerst, J., Kataoka, T., Michaeli, T., Powers, S., Riggs, M., Rodgers, L., Wieland, L, Wheland, B., and Wigler, M., 1990, Cloning and characterization of CAP, the S. cerevisiae gene encoding the 70 kd adenylyl cyclase-associated protein, Cell, 61: 319.PubMedCrossRefGoogle Scholar
  19. François, J., Van Schaftingen, E., and Hers, H. B., 1984, The mechanism by which glucose increases fructose-2,6-bisphosphate concentration in Saccharomyces cerevisiae. A cyclic-AMP-dependent activation of phosphofructokinase 2, Eur. J. Biochem., 145: 187.PubMedCrossRefGoogle Scholar
  20. François, J., Villanueva, M. E., and Hers, H. G., 1988, The control of glycogen metabolism in yeast. 1. Interconversion in vivo of glycogen synthase and glycogen Phosphorylase induced by glucose, a nitrogen source or uncouplers, Eur. J. Biochem., 174: 551.PubMedCrossRefGoogle Scholar
  21. Gibbs, J. B., and Marshall, M. S., 1989, The ras oncogene — an important regulatory element in lower eucaryotic organisms, Microbiol. Rev., 53: 171.PubMedGoogle Scholar
  22. Goffeau, A., and Slayman, C. W., 1981, The proton-translocating ATPase of the fungal plasma membrane, Biochim. Biophys. Acta, 639: 197.PubMedGoogle Scholar
  23. Holzer, H., 1984, Mechanism and function of reversible phosphorylation of fructose 1,6-bisphosphatase in yeast, in “Molecular aspects of cellular regulation, Vol. 3”, P. Cohen, ed., Elsevier, Amsterdam.Google Scholar
  24. Lopez-Boado, Y. S., Herrero, P., Gascon, S., and Moreno, F., 1987, Catabolite inactivation of isocitrate lyase from Saccharomyces cerevisiae, Arch. Microbiol., 147: 231.PubMedCrossRefGoogle Scholar
  25. Lopez-Boado, Y. S., Herrero, P., Fernandez, T., Fernandez R., and Moreno, F., 1988, Glucose-stimulated phosphorylation of yeast isocitrate lyase in vivo, J. Gen. Microbiol., 134: 2499.PubMedGoogle Scholar
  26. Matsumoto, K., Uno, I., Toh-e, A., Ishikawa, T., and Oshima, Y., 1982, Cyclic AMP may not be involved in catabolite repression in Saccharomyces cerevisiae: evidence from mutants capable of utilizing it as an adenine source, J. Bacteriol, 150: 277.PubMedGoogle Scholar
  27. Matsumoto, K., Uno, I., and Ishikawa, K., 1985, Genetic analysis of the role of cAMP in yeast, Yeast, 1: 15.PubMedCrossRefGoogle Scholar
  28. Mazon, M. J., Gancedo, J. M., and Gancedo, C., 1982, Phosphorylation and inactivation of yeast fructose-bisphosphatase in vivo by glucose and by proton ionophores. A possible role for cAMP, Eur. J. Biochem., 127: 605.PubMedCrossRefGoogle Scholar
  29. Mbonyi, K., and Thevelein, J. M., 1988, The high-affinity glucose uptake system is not required for induction of the RAS-mediated cAMP signal by glucose in cells of the yeast Saccharomyces cerevisiae, Biochim. Biophys. Acta, 971:223.PubMedCrossRefGoogle Scholar
  30. Mbonyi, K., Beullens, M., Detremerie, K., Geerts, L., and Thevelein, J. M., 1988, Requirement of one functional RAS gene and inability of an oncogenic ras-variant to mediate the glucose-induced cAMP signal in the yeast Saccharomyces cerevisiae, Mol Cell Biol, 8:3051.PubMedGoogle Scholar
  31. Mbonyi, K., Van Aelst, L., Argüelles, J. C., Jans, A. W. H., and Thevelein, J. M., 1990, Glucose-induced hyperaccumulation of cAMP and absence of glucose repression in yeast strains with reduced activity of cAMP-dependent protein kinase, Mol Cell. Biol, 10:4518.PubMedGoogle Scholar
  32. Münder, T., and Küntzel, H., 1989, Glucose-induced cAMP signaling in Saccharomyces cerevisiae is mediated by the CDC25 protein, FEBS Lett., 242:341.PubMedCrossRefGoogle Scholar
  33. Neigeborn, L., Schwartzberg, P., Reid, R., Carlson, M., 1986, Null mutations in the SN F 3 gene of Saccharomyces cerevisiae cause a different phenotype than do previously isolated missense mutations, Mol Cell Biol, 6: 3569.PubMedGoogle Scholar
  34. Nikawa, J., Cameron, S., Toda, T., Ferguson, K. W., and Wigler, M., 1987a, Rigorous feedback control of cAMP levels in Saccharomyces cerevisiae, Gen. Develop., 1: 931.CrossRefGoogle Scholar
  35. Nikawa, J., Sass, P., and Wigler, M., 1987b, Cloning and characterization of the low-affinity cyclic AMP phosphodiesterase gene of Saccharomyces cerevisiae, Mol. Cell. Biol, 7: 3629.PubMedGoogle Scholar
  36. Pascual, C., Alonso, A., Garcia, I., Romay, C., and Kotyk, A., 1988, Effect of ethanol on glucose transport, key glycolytic enzymes and proton extrusion in Saccharomyces cerevisiae, Biotechnol. Bioeng., 32: 374.PubMedCrossRefGoogle Scholar
  37. Peinado, J. M., and Loureiro-Dias, M. C., 1986, Reversible loss of affinity induced by glucose in the maltose — H+ symport of Saccharomyces cerevisiae, Biochim. Biophys. Acta, 856: 189.PubMedCrossRefGoogle Scholar
  38. Praekelt, U. M., and Meacock, P. A., 1990, HSP12, a new small heat shock gene of Saccharomyces cerevisiae: Analysis of structure, regulation and function, Mol. Gen. Genet., 223: 97.PubMedCrossRefGoogle Scholar
  39. Pringle, J. H., and Hartwell, L. H., 1981, The Saccharomyces cerevisiae cell cycle, in: “The Molecular biology of the yeast Saccharomyces. Life cycle and inheritance.”, J. N. Strathern, E. W. Jones, and J. R. Broach, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor.Google Scholar
  40. Purwin, C., Leidig, F., and Holzer, H., 1982, Cyclic AMP-dependent phosphorylation of fructose 1,6-bisphosphatase in yeast, Biochem. Biophys. Res. Commun., 107: 1482.PubMedCrossRefGoogle Scholar
  41. Purwin, C., Nicolay, K., Scheffers, W. A., and Holzer, H., 1986, Mechanism of control of adenylate cyclase activity in yeast by fermentable sugars and carbonyl cyanide m-chlorophenylhydrazone, J. Biol. Chem., 261: 8744.PubMedGoogle Scholar
  42. Sass, P., Field, J., Nikawa, J., Toda, T., and Wigler, M., 1986, Cloning and characterization of the high-affinity cAMP phosphodiesterase of S. cerevisiae, Proc. Natl. Acad. Sci. (USA), 83:9303.CrossRefGoogle Scholar
  43. Serrano, R., 1984, Plasma membrane ATPase of fungi and plants as a novel type of proton pump, Curr. Top. Cell. Reg., 23: 87.Google Scholar
  44. Tanaka, K., Matsumoto, K., and Tohe, A., 1988, Dual regulation of the expression of the polyubiquitin gene by cyclic AMP and heat shock in yeast, EMBO J., 7: 495.PubMedGoogle Scholar
  45. Tanaka, K., Matsumoto, K., and Tohe, A., 1989, Iral, an inhibitory regulator of the RAS — cyclic AMP pathway in Saccharomyces cerevisiae, Mol. Cell. Biol., 9: 757.PubMedGoogle Scholar
  46. Tanaka, K., Nakafuku, M., Tamanoi, F., Kaziro, Y., Matsumoto, K. and Tohe, A., 1990, IRA2, a second gene of Saccharomyces cerevisiae that encodes a protein with a domain homologous to mammalian ras GTPase-activating protein, Mol. Cell. Biol, 10:4303.PubMedGoogle Scholar
  47. Thevelein, J. M., 1984a, Cyclic — AMP content and trehalase activation in vegetative cells and ascospores of yeast, Arch. Microbiol., 138: 64.PubMedCrossRefGoogle Scholar
  48. Thevelein, J. M., 1984b, Regulation of trehalose mobilization in fungi, Microbiol. Rev., 48:42.PubMedGoogle Scholar
  49. Thevelein, J. M., 1988, Regulation of trehalase activity by phosphorylation -dephosphorylation during developmental transitions in fungi, Exp. Mycol., 12: 1.CrossRefGoogle Scholar
  50. Thevelein, J. M., and Beullens, M., 1985, Cyclic AMP and the stimulation of trehalase activity in the yeast Saccharomyces cerevisiae by carbon sources, nitrogen sources and inhibitors of protein synthesis, J. Gen. Microbiol., 131:3199.PubMedGoogle Scholar
  51. Thevelein, J. M., Beullens, M., Honshoven, F., Hoebeeck, G., Detremerie, K., den Hollander, J. A., and Jans, A. W. H., 1987a, Regulation of the cAMP level in the yeast Saccharomyces cerevisiae: intracellular pH and the effect of membrane depolarizing compounds, J. Gen. Microbiol., 133:2191.PubMedGoogle Scholar
  52. Thevelein, J. M., Beullens, M., Honshoven, F., Hoebeeck, G., Detremerie, K., Griewel, B., den Hollander, J. A., and Jans, A. W. H., 1987b, Regulation of the cAMP level in the yeast Saccharomyces cerevisiae: the glucose-induced cAMP signal is not mediated by a transient drop in the intracellular pH, J. Gen. Microbiol., 133: 2197.PubMedGoogle Scholar
  53. Toda, T., Uno, I., Ishikawa, T., Powers, S., Kataoka, T., Broek, D., Cameron, S., Broach, J., Matsumoto, K., and Wigler, M., 1985, In yeast, Ras proteins are controlling elements of adenylate cyclase, Cell, 40: 27.PubMedCrossRefGoogle Scholar
  54. Toda, T., Cameron, S., Sass, P., Zoller, M., and Wigler, M., 1987a, Three different genes in Saccharomyces cerevisiae encode the catalytic subunits of the cAMP-dependent protein kinase, Cell, 50: 277.PubMedCrossRefGoogle Scholar
  55. Toda, T., Cameron, S., Sass, P., Zoller, M., Scott, J. D., McBullen, B., Hurwitz, M., Krebs, E. G., and Wigler, M., 1987b, Cloning and characterization of BCY1, a locus encoding a regulatory subunit of the cyclic AMP-dependent protein kinase in Saccharomyces cerevisiae, Mol. Cell. Biol., 7: 1371.PubMedGoogle Scholar
  56. Tortora, P., Burlini, N., Caspani, G., and Guerritore, A., 1984, Studies on glucose -induced inactivation of gluconeogenetic enzymes in adenylate cyclase and cAMP-dependent protein kinase yeast mutants, Eur. J. Biochem., 145: 543.PubMedCrossRefGoogle Scholar
  57. Van Aelst, L., Boy-Marcotte, E., Camonis, J. H., Thevelein, J. M., and Jacquet, M., 1990, The C-terminal part of the CDC25 gene product plays a key role in signal transduction in the glucose-induced modulation of cAMP level in Saccharomyces cerevisiae, Eur. J. Biochem., 193: 675.PubMedCrossRefGoogle Scholar
  58. Van Aelst, L., Jans, A. W. H., and Thevelein, J. M., 1991a, Involvement of the CDC25 gene product in the signal transmission pathway of the glucose-induced RAS-mediated cAMP signal in the yeast Saccharomyces cerevisiae, J. Gen. Microbiol., 137: 341.PubMedGoogle Scholar
  59. Van Aelst, L., Hohmann, S., Zimmermann, F. K., Jans, A. W. H., and Thevelein, J. M., 1991b, A yeast homologue of the bovine lens fiber MIP gene family complements the growth defect of a Saccharomyces cerevisiae mutant on fermentable sugars but not its defect in glucose-induced RAS-mediated cAMP signaling, EMBO J., 10: in press.Google Scholar
  60. van de Poll, K. W., Kerkenaar, A., and Schamhart, D. H. J., 1974, Isolation of a regulatory mutant of fructose-l,6-diphosphatase in Saccharomyces carlsbergensis, J. Bacteriol., 117: 965.PubMedGoogle Scholar
  61. Verdier, J. M. et al., 1989, Cloning of CDC33: a gene essential for growth and sporulation which does not interfere with cAMP production of Saccharomyces cerevisiae, Yeast, 5: 79–90.PubMedCrossRefGoogle Scholar
  62. Werner-Washburne, M., Becker, J., Kosic-Smithers, J., and Craig, E.A., 1989, Yeast Hsp70 RNA levels vary in response to the physiological status of the cell, J. Bacteriol., 171: 2680.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Johan M. Thevelein
    • 1
  • Linda Van Aelst
    • 1
  • Peter Durnez
    • 1
  • Stefan Hohmann
    • 1
  1. 1.Laboratorium voor Cellulaire BiochemieKatholieke Universiteit te LeuvenLeuven-Heverlee, FlandersBelgium

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