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:

The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation

Oncogene volume 21, pages 1750–1758 (2002)Cite this article

Abstract

Apoptosis is closely linked to proliferation. In this study we showed that inducing apoptosis in mouse mesangial cells with ultraviolet (UV) irradiation was associated with increased cyclin A-cyclin dependent kinase (CDK) 2 activity. Inhibiting CDK2 activity with Roscovitine or dominant negative mutant reduced apoptosis. Because apoptosis typically begins in the cytoplasm, we tested the hypothesis that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell. Our results showed that cyclin A-CDK2 was nuclear in proliferating cells. However, inducing apoptosis in proliferating cells with UV irradiation was associated with a decrease in nuclear cyclin A and CDK2 protein levels. This coincided with an increase in protein and kinase activity for cyclin A-CDK2 in the cytoplasm. Translocation of cyclin A-CDK2 also occurred in p53−/− mesangial cells. Finally, we showed that caspase-3 activity was significantly reduced by inhibiting CDK2 activity with Roscovitine. In summary, our results show that apoptosis is associated with an increase in cytoplasmic cyclin A-CDK2 activity, which is p53 independent and upstream of caspase-3. We propose that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell.

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
Figure 6
Figure 7

Similar content being viewed by others

References

  • Adachi S, Ito H, Tamamori-Adachi M, Ono Y, Nozato T, Abe S, Ikeda M, Marumo F, Hiroe M . 2001 Circ. Res. 88: 408–414

  • Baker AJ, Mooney A, Hughes J, Lombardi D, Johnson RJ, Savill J . 1994 J. Clin. Invest. 94: 2105–2116

  • Baptist M, Lamy F, Gannon J, Hunt T, Dumont JE, Roger PP . 1996 J. Cell Physiol. 166: 256–273

  • Bomsztyk K, Van Seuningen I, Suzuki H, Denisenko O, Ostrowski J . 1997 FEBS Lett. 403: 113–115

  • Bortner DM, Rosenberg MP . 1995 Cell Growth Differ. 6: 1579–1589

  • Bresnahan WA, Boldogh I, Ma T, Albrecht T, Thompson EA . 1996 Cell Growth Differ. 7: 1283–1290

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B . 1999 Nature 401: 616–620

  • Chao DT, Korsmeyer SJ . 1998 Annu. Rev. Immunol. 16: 395–419

  • Danno K, Horio T . 1982 Br. J. Dermatol. 107: 423–428

  • Dobashi Y, Shoji M, Kondo E, Akiyama T, Kameya T . 1998 Biochem. Biophys. Res. Commun. 253: 609–613

  • Furuno N, den Elzen N, Pines J . 1999 J. Cell. Biol. 147: 295–306

  • Gil-Gomez G, Berns A, Brady HJ . 1998 EMBO J 17: 7209–7218

  • Green DR, Reed JC . 1998 Science 281: 1309–1312

  • Hakem A, Sasaki T, Kozieradzki I, Penninger JM . 1999 J. Exp. Med. 189: 957–968

  • Harvey KJ, Lukovic D, Ucker DS . 2000 J. Cell. Biol. 148: 59–72

  • Hiromura K, Pippin JW, Fero ML, Roberts JM, Shankland SJ . 1999 J. Clin. Invest. 103: 597–604

  • Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV . 1994 Proc. Natl. Acad. Sci. USA 91: 6875–6879

  • Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R . 1998 Mol. Cell 1: 553–563

  • Martin SJ, Cotter TG . 1991 Int. J. Radiat. Biol. 59: 1001–1016

  • Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG, Moulinoux JP . 1997 Eur. J. Biochem. 243: 527–536

  • Meikrantz W, Gisselbrecht S, Tam SW, Schlegel R . 1994 Proc. Natl. Acad. Sci. USA 91: 3754–3758

  • Meikrantz W, Schlegel R . 1996 J. Biol. Chem. 271: 10205–10209

  • Miller LJ, Marx J . 1998 Science 281: 1301–

  • Minn AJ, Swain RE, Ma A, Thompson CB . 1998 Adv. Immunol. 70: 245–279

  • Mooney A, Jobson T, Bacon R, Kitamura M, Savill J . 1997 J. Immunol. 159: 3949–3960

  • Moore JD, Yang J, Truant R, Kornbluth S . 1999 J. Cell. Biol. 144: 213–224

  • Nishioka WK, Welsh RM . 1994 J. Exp. Med. 179: 769–774

  • Ophascharoensuk V, Fero ML, Hughes J, Roberts JM, Shankland SJ . 1998 Nat. Med. 4: 575–580

  • Orend G, Hunter T, Ruoslahti E . 1998 Oncogene 16: 2575–2583

  • Pagano M, Pepperkok R, Lukas J, Baldin V, Ansorge W, Bartek J, Draetta G . 1993 J. Cell Biol. 121: 101–111

  • Park DS, Morris EJ, Padmanabhan J, Shelanski ML, Geller HM, Greene LA . 1998 J. Cell Biol. 143: 457–467

  • Pines J . 1994 Semin. Cancer Biol. 5: 305–313

  • Pippin JW, QU Q, Meijer L, Shankland SJ . 1997 J. Clin. Invest. 100: 2512–2520

  • Reed SI . 1997 Cancer Surv. 29: 7–23

  • Roussel MF . 1998 Adv. Cancer Res. 74: 1–24

  • Shankland SJ, Wolf G . 2000 Am. J. Physiol. Renal. Physiol. 278: F515–F529

  • Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512

  • Shi L, Nishioka WK, Th'ng J, Bradbury EM, Litchfield DW, Greenberg AH . 1994 Science 263: 1143–1145

  • Syljuasen RG, McBride WH . 1999 Radiat. Res. 152: 328–331

  • Toyoshima F, Moriguchi T, Wada A, Fukuda M, Nishida E . 1998 EMBO J. 17: 2728–2735

  • Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW . 1998 Genes Dev. 12: 806–819

  • Yang J, Bardes ES, Moore JD, Brennan J, Powers MA, Kornbluth S . 1998 Genes Dev. 12: 2131–2143

  • Yao SL, McKenna KA, Sharkis SJ, Bedi A . 1996 Cancer Res. 56: 4551–4555

  • Yoshida M, Horinouchi S . 1999 Ann. NY Acad. Sci. 886: 23–36

Download references

Acknowledgements

This work was supported by Public Health Service grants (DK34198, DK52121, DK51096, DK56799) and a George M O'Brien Kidney Center Grant (DK47659). JM Roberts is an Investigator of the Howard Hughes Medical Institute. K Hiromura was supported by the Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, 98195-6521, Washington, WA, USA

    K Hiromura, J W Pippin, M J Blonski & S J Shankland

  2. Department of Basic Sciences and Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, 98104, Washington, WA, USA

    J M Roberts

Authors
  1. K Hiromura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J W Pippin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M J Blonski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J M Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S J Shankland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S J Shankland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hiromura, K., Pippin, J., Blonski, M. et al. The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene 21, 1750–1758 (2002). https://doi.org/10.1038/sj.onc.1205238

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205238

Keywords

This article is cited by

Search

Advanced search

Quick links