Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2

Oncogene volume 18, pages 573–582 (1999)Cite this article

Abstract

The cdc25A phosphatase removes inhibitory phosphates from threonine-14 and tyrosine-15 of cyclin dependent kinase-2 (cdk2) in vitro, and it is therefore widely assumed that cdc25A positively regulates cyclin E- and A-associated cdk2 activity at the G1 to S phase transition of the mammalian cell division cycle. Human cdc25A was introduced into mouse NIH3T3 fibroblasts co-expressing a form of the colony-stimulating factor-1 (CSF-1) receptor that is partially defective in transducing mitogenic signals. Cdc25A enabled these cells to form colonies in semisolid medium containing serum plus human recombinant CSF-1 in a manner reminiscent of cells rescued by c-myc. However, cdc25A-rescued cells could not proliferate in chemically defined medium containing CSF-1 and continued to require c-myc function for S phase entry. When contact-inhibited cells overexpressing cdc25A were dispersed and stimulated to synchronously enter the cell division cycle, they entered S phase 2 – 3 h earlier than their parental untransfected counterparts. Shortening of G1 phase temporally correlated with more rapid degradation of the cdk inhibitor p27Kip1 and with premature activation of cyclin A-dependent cdk2. Paradoxically, tyrosine phosphorylation of cdk2 increased considerably as cells entered S phase, and cdc25A overexpression potentiated rather than diminished this effect. At face value, these results are inconsistent with the hypothesis that cdc25A acts directly on cdk2 to activate its S phase promoting function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Atherton-Fessler S, Parker LL, Geahlen RL and Piwnica-Worms H. . 1993 Mol. Cell. Biol. 13: 1675–1685.

  • Boyle WJ, Van der Geer P and Hunter T. . Methods in Enzymology: Protein phosphorylation, Part B . Hunter T and Sefton BO . (201): pp 21–27.1991 Academic Press.

    Google Scholar 

  • Cheng M, Sexl V, Sherr CJ and Roussel MF. . 1998 Proc. Natl. Acad. Sci. USA 95: 1091–1096.

  • Connell-Crowley L, Harper JW and Goodrich DW. . 1997 Mol. Biol. Cell. 8: 287–301.

  • Diehl JA, Zindy F and Sherr CJ. . 1997 Genes Dev. 11: 957–972.

  • Draetta G and Eckstein J. . 1997 Biochem. Biophys. Acta. 1332: 53–63.

  • Eilers M, Schirm S and Bishop JM. . 1991 EMBO J. 10: 133–141.

  • Elledge SJ and Harper JW. . 1994 Curr. Opin. Cell. Biol. 6: 847–852.

  • Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J-Y and Livingston DM. . 1993 Cell 73: 487–497.

  • Fisher RP and Morgan DO. . 1994 Cell 78: 713–724.

  • Furnari B, Rhind N and Russell P. . 1997 Science 277: 1495–1497.

  • Galaktionov K, Jessus C and Beach D. . 1995a Genes Dev. 9: 1046–1058.

  • Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M and Beach D. . 1995b Science 269: 1575–1577.

  • Galaktionov K and Beach D. . 1991 Cell 67: 1181–1194.

  • Galaktionov K, Chen X and Beach D. . 1996 Nature 382: 511–517.

  • Gautier J, Solomon MJ, Booher RN, Bazan JF and Kirschner MW. . 1991 Cell 67: 197–221.

  • Gu Y, Rosenblatt J and Morgan DO. . 1992 EMBO J. 11: 3995–4005.

  • Hatakeyama M, Brill JA, Fink GR and Weinberg RA. . 1994 Genes Dev. 8: 1759–1771.

  • Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI and Weinberg RA. . 1992 Cell 70: 993–1006.

  • Hoffmann I, Clarke P, Marcote MJ, Karsenti E and Draetta G. . 1993 EMBO J 12: 1549–1556.

  • Hoffmann I, Draetta G and Karsenti E. . 1994 EMBO J. 13: 4302–4310.

  • Iavarone A and Massagué J. . 1997 Nature 387: 417–422.

  • Jinno S, Suto K, Nagata A, Igarashi M, Kanaoka Y, Nojima H and Okayama H. . 1994 EMBO J. 13: 1549–1556.

  • Karn J, Watson JV, Lowe AD, Green SM and Vedeckis W. . 1989 Oncogene 4: 773–787.

  • Kato J-Y, Matsushime H, Hiebert S, Ewen ME and Sherr CJ. . 1993 Genes Dev. 7: 331–342.

  • Kato J, Matsuoka M, Polyak K, Massagué J and Sherr CJ. . 1994 Cell 79: 487–496.

  • King RW, Jackson PK and Kirschner MW. . 1994 Cell 79: 563–571.

  • Krek W and Nigg EA. . 1991 EMBO J. 10: 305–316.

  • Krude T, Jackman M, Pines J and Laskey RA. . 1997 Cell 88: 109–119.

  • Lew DJ and Kornbluth S. . 1996 Curr. Opin. Cell. Biol. 8: 795–804.

  • Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI and Bartek J. . (1997) Genes Dev. 11: 1479–1492.

  • Lundberg AS and Weinberg RA. . 1998 Mol. Cell. Biol. 18: 753–761.

  • Lundgren K, Walworth N, Booher R, Dembski M, Kirschner M and Beach D. . 1991 Cell 64: 1111–1122.

  • Makela TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ and Weinberg RA. . 1994 Nature 371: 254–257.

  • Matsuoka M, Kato J, Fisher RP, Morgan DO and Sherr CJ. . 1994 Mol. Cell. Biol. 14: 7265–7275.

  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato J-Y. . 1994 Mol. Cell. Biol. 14: 2066–2076.

  • Matsushime H, Roussel MF, Ashmun RA and Sherr CJ. . 1991 Cell 65: 701–713.

  • McGowan CH and Russell P. . 1995 EMBO J. 14: 2166–2175.

  • Meyerson M and Harlow E. . 1994 Mol. Cell. Biol. 14: 2077–2086.

  • Morgan DO. . 1995 Nature 374: 131–134.

  • Morgenstern JP and Land H. . 1990 Nucleic Acids Res. 18: 1068–1077.

  • Nagata A, Igarashi M, Jinno S, Suto K and Okayama H. . 1991 New Biol. 3: 959–968.

  • Norbury C and Nurse P. . 1992 Annu. Rev. Biochem. 61: 441–470.

  • Nurse P. . 1994 Cell 79: 547–550.

  • Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM and Pagano M. . 1995 Mol. Cell. Biol. 15: 2612–2624.

  • Pagano M, Tam SW, Theodoras AM, Beer-Romano P, Dal Sal G, Chau V, Yew PR, Draetta GF and Rolfe M. . 1995 Science 269: 682–685.

  • Peng C-Y, Graves PR, Thoma RS, Wu Z, Shaw AS and Piwnica-Worms H. . 1997 Science 277: 1501–1505.

  • Peters G. . 1994 Nature 371: 204–205.

  • Pines J. . 1993 Trends Biochem. Sci. 18: 195–197.

  • Polyak K, Kato J-Y, Solomon MJ, Sherr CJ, Massagué J, Roberts JM and Koff A. . 1994 Genes Dev. 8: 9–22.

  • Reed SI. . 1992 Annu. Rev. Cell. Biol. 8: 529–561.

  • Reynisdottir I and Massagué J. . 1997 Genes Dev. 11: 492–503.

  • Roussel MF, Cleveland JL, Shurtleff SA and Sherr CJ. . 1991 Nature 353: 361–363.

  • Roussel MF and Sherr CJ. . 1989 Proc. Natl. Acad. Sci. USA 86: 7924–7927.

  • Roussel MF, Shurtleff SA, Downing JR and Sherr CJ. . 1990 Proc. Natl. Acad. Sci. USA 87: 6738–6742.

  • Roussel MF, Theodoras AM, Pagano M and Sherr CJ. . 1995 Proc. Nat. Acad. Sci. USA 92: 6837–6841.

  • Saha P, Eichbaum Q, Silberman ED, Mayer BJ and Dutta A. . 1997 Mol. Cell. Biol. 17: 4338–4345.

  • Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H and Elledge SJ. . 1997 Science 277: 1497–1501.

  • Sandhu K, Reed SI, Richardson H and Russell P. . 1990 Proc. Nat. Acad. Sci. USA. 87: 5139–5143.

  • Sheaff R, Groudine M, Gordon M, Roberts J and Clurman B. . 1997 Genes Dev. 11: 1464–1478.

  • Sherr CJ. . 1993 Cell 73: 1059–1065.

  • Sherr CJ. . 1994 Cell 79: 551–555.

  • Sherr CJ and Roberts JM. . 1995 Genes Dev. 9: 1149–1163.

  • Stillman B. . 1996 Science 274: 1659–1664.

  • Terada Y, Tatsuka M, Jinno S and Okayama H. . 1995 Nature 376: 358–362.

  • Tiefenbrun N., Melamed D, Levy N, Resnitzky D, Hoffmann I, Reed SI and Kimchi A. . 1996 Mol. Cell. Biol. 16: 3934–3944.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Xu X and Burke SP. . 1996 J Biol. Chem. 271: 5118–5124.

Download references

Acknowledgements

We are indebted to Joseph Watson, Shawn Hawkins, Carol Bockhold and Sam Lucas for excellent technical assistance, and we thank Giulio Draetta, Ben Neel and Nicholas Tonks for helpful suggestions during the course of this work. We also thank our colleagues for their support, helpful discussions, and criticisms, and particularly, Drs Frederique Zindy, Mangeng Cheng and Richard Moriggl. This work was supported in part by NIH CA-56819 (MFR), Cancer Center (CORE) Support Grant CA-21765, Howard Hughes Medical Institute (CJS) and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children's Research Hospital. VS is a fellow of the Austrian Fond zur Foerderung der Wissenschaftlichen Forschung (FWF).

Author information

Authors and Affiliations

  1. Department of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Veronika Sexl, J Alan Diehl, Charles J Sherr & Martine F Roussel

  2. Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Richard Ashmun

  3. Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    J Alan Diehl & Charles J Sherr

  4. Institute of Child Health, London, WC1N 1EH, UK

    David Beach

Authors
  1. Veronika Sexl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Alan Diehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles J Sherr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Ashmun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Beach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martine F Roussel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sexl, V., Diehl, J., Sherr, C. et al. A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2. Oncogene 18, 573–582 (1999). https://doi.org/10.1038/sj.onc.1202362

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202362

Keywords

This article is cited by

Search

Advanced search

Quick links