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Yeast G1 cyclins are unstable in G1 phase

Abstract

In most eukaryotes, commitment to cell division occurs in late G1 phase at an event called Start in the yeast Saccharomyces cerevisiae1, and called the restriction point in mammalian cells2. Start is triggered by the cyclin-dependent kinase Cdc28 and threerate-limiting activators, the G1 cyclins Cln1, Cln2 and Cln3 (ref. 3). Cyclin accumulation in G1 is driven in part by the cell-cycle-regulated transcription of CLN1 and CLN2, which peaks at Start3. CLN transcription is modulated by physiological signals that regulate G1 progression4,5, but it is unclear whether Cln protein stability is cell-cycle-regulated. It has been suggested that once cells pass Start, Cln proteolysis is triggered by the mitotic cyclins Clb1, 2, 3 and 4 (ref. 6). But here we show that G1 cyclins are unstable in G1 phase, and that Clb–Cdc28 activity is not needed for G1 cyclin turnover. Cln instability thus provides a means to couple Cln–Cdc28 activity to transcriptional regulation and protein synthetic rate in pre-Start G1 cells.

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Figure 1: Cln2 is unstable in G1 phase.
Figure 2: Clb activity is not required for Cln2 degradation.
Figure 3: Sic1 accumulation does not affect Cln2 stability.

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References

  1. Hartwell, L. H., Culotti, J., Pringle, J. R. & Reid, B. J. Genetic control of the cell division cycle in yeast. Science 183, 46–51 (1974).

    Article  ADS  CAS  Google Scholar 

  2. Rossow, P. W., Riddle, V. G. & Pardee, A. B. Synthesis of labile, serum-dependent protein in early G1 controls animal cell growth. Proc. Natl Acad. Sci. USA 76, 4446–4450 (1979).

    Article  ADS  CAS  Google Scholar 

  3. Cross, F. R. Starting the cell cycle: what's the point? Curr. Opin. Cell Biol. 7, 790–797 (1995).

    Article  CAS  Google Scholar 

  4. Baroni, M. D., Monti, P. & Alberghina, L. Repression of growth-regulated G1 cyclin expression by cyclic AMP in budding yeast. Nature 371, 339–342 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Tokiwa, G., Tyers, M., Volpe, T. & Futcher, B. Inhibition of G1 cyclin activity by the Ras/cAMP pathway in yeast. Nature 371, 342–345 (1994).

    Article  ADS  CAS  Google Scholar 

  6. Blondel, M. & Mann, C. G2 cyclins are required for the degradation of G1 cyclins in yeast. Nature 384, 279–282 (1996).

    Article  ADS  CAS  Google Scholar 

  7. Tyers, M., Tokiwa, G., Nash, R. & Futcher, B. The Cln3–Cdc28 kinase complex of S. cerevisiae is regulated by proteolysis and phosphorylation. EMBO J. 11, 1773–1784 (1992).

    Article  CAS  Google Scholar 

  8. Cross, F. R. & Blake, C. M. The yeast Cln3 protein is an unstable activator of Cdc28. Mol. Cell. Biol. 13, 3266–3271 (1993).

    Article  CAS  Google Scholar 

  9. Salama, S. R., Hendricks, K. B. & Thorner, J. G1 cyclin degradation: the PEST motif of yeast Cln2 is necessary, but not sufficient, for rapid protein turnover. Mol. Cell. Biol. 14, 7953–7966 (1994).

    Article  CAS  Google Scholar 

  10. Yaglom, J. et al. p34Cdc28-mediated control of Cln3 cyclin degradation. Mol. Cell. Biol. 15, 731–741 (1995).

    Article  CAS  Google Scholar 

  11. Deshaies, R. J., Chau, V. & Kirschner, M. Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. EMBO J. 14, 303–312 (1995).

    Article  CAS  Google Scholar 

  12. Lanker, S., Valdivieso, M. H. & Wittenberg, C. Rapid degradation of the G1 cyclin Cln2 induced by CDK-dependent phosphorylation. Science 271, 1597–1601 (1996).

    Article  ADS  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Willems, A. R. et al. Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. Cell 86, 453–463 (1996).

    Article  CAS  Google Scholar 

  15. Tyers, M. & Futcher, B. Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes. Mol. Cell. Biol. 13, 5659–5669 (1993).

    Article  CAS  Google Scholar 

  16. Valdivieso, M. H., Sugimoto, K., Jahng, K. Y., Fernandes, P. M. & Wittenberg, C. FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone. Mol. Cell. Biol. 13, 1013–1022 (1993).

    Article  CAS  Google Scholar 

  17. Amon, A., Irniger, S. & Nasmyth, K. Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. Cell 77, 1037–1050 (1994).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Verma, R. et al. Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. Science 278, 455–460 (1997).

    Article  ADS  CAS  Google Scholar 

  21. Nugroho, T. T. & Mendenhall, M. D. An inhibitor of yeast cyclin-dependent protein kinase plays an important role in ensuring the genomic integrity of daughter cells. Mol. Cell. Biol. 4, 3320–3328 (1994).

    Article  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. Feldman, R. M., Correll, C. C., Kaplan, K. B., Deshaies, R. J. Acomplex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91, 221–230 (1997).

    Article  CAS  Google Scholar 

  24. Patton, E. E. et al. Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box protein complexes that regulate cell division and methionine biosynthesis in yeast. Genes Dev. 12, 692–705 (1998).

    Article  CAS  Google Scholar 

  25. Ko, H. A. & Moore, S. A. Kinetic characterization of a prestart cell division control step in yeast. Implications for the mechanism of alpha-factor-induced division arrest. J. Biol. Chem. 265, 21652–21663 (1990).

    CAS  PubMed  Google Scholar 

  26. Zetterberg, A. & Larsson, O. Coordination between cell growth and cell cycle transit in animal cells. Cold Spring Harb. Symp. Quant. Biol. 56, 137–147 (1991).

    Article  CAS  Google Scholar 

  27. Clurman, B. E., Sheaff, R. J., Thress, K., Groudine, M. & Roberts, J. M. Turnover of cyclin E by the ubiquitin–proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev. 10, 1979–1990 (1996).

    Article  CAS  Google Scholar 

  28. Diehl, J. A., Zindy, F. & Sherr, C. J. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin–proteasome pathway. Genes Dev. 11, 957–972 (1997).

    Article  CAS  Google Scholar 

  29. Won, K. A. & Reed, S. I. Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E. EMBO J. 15, 4182–4193 (1996).

    Article  CAS  Google Scholar 

  30. Wittenberg, C., Sugimoto, K. & Reed, S. I. G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase. Cell 62, 225–237 (1990).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Amon for advice on pulse–chase experiments, E. Schwob and K.Nasymth for strains, and C. Mann, M. Blondel and D. Kornitzef for sharing unpublished data and many helpful discussions. B.S. was supported by an Army Breast Cancer post-doctoral fellowship, E.P. by an National Sciences and Engineering Research Council pre-doctoral fellowship, and S.L. by the Swiss National Science Foundation and the Human Frontiers in Science program. M.D.M., C.W. and B.F. are supported by grants from the NIH, and M.T. is supported by grants from the Medical Research Council of Canada and the National Cancer Institute of Canada (NCIC) and is a Research Scientist of the NCIC.

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Correspondence to Mike Tyers.

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Schneider, B., Patton, E., Lanker, S. et al. Yeast G1 cyclins are unstable in G1 phase. Nature 395, 86–89 (1998). https://doi.org/10.1038/25774

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