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:

Difference in the centrosome duplication regulatory activity among p53 ‘hot spot’ mutants: potential role of Ser 315 phosphorylation-dependent centrosome binding of p53

Oncogene volume 20, pages 6851–6863 (2001)Cite this article

Abstract

The p53 tumor suppressor protein regulates centrosome duplication through multiple pathways, and p21Waf1/Cip1 (Waf1), a major target of p53's transactivation function, has been shown to be one of the effectors. However, it had been unclear whether the p53's Waf1-independent centrosome duplication regulatory pathways require its transactivation function. In human cancers, specific residues of p53 are mutated at a high frequency. These ‘hot spot’ mutations abrogate p53's transactivation function. If p53 regulates centrosome duplication in a transactivation-independent manner, different ‘hot spot’ mutants may regulate centrosome duplication differently. To test this, we examined the effect of two ‘hot spot’ mutants (R175H and R249S) for their centrosome duplication regulatory activities. We found that R175H lost the ability to regulate centrosome duplication, while R249S partially retained it. Moreover, R249S associates with both unduplicated and duplicated centrosomes similar to wild-type p53, while R175H only associates with duplicated, but not unduplicated centrosomes. Since cyclin-dependent kinase 2 (CDK2) triggers initiation of centrosome duplication, and p53 is phosphorylated on Ser 315 by CDK2, we examined the p53 mutants with a replacement of Ser 315 to Ala (A) and Asp (D), both of which retain the transactivation function. We found that S315D retained a complete centrosome duplication activity, while S315A only partially retained it. Moreover, S315D associates with both unduplicated and duplicated centrosomes, while S315A associates with only duplicated, but not unduplicated centrosomes. Thus, p53 controls the centrosome duplication cycle both in transactivation-dependent and transactivation-independent manners, and the ability to bind to unduplicated centrosomes, which is controlled by phosphorylation on Ser 315, may be important for the overall p53-mediated regulation of centrosome duplication.

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
Figure 8

Similar content being viewed by others

References

  • Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug JE, Akslen LA, Lonning PE . 1996 Nature Med. 2: 811–814

  • Ahnen DJ . 1992 J. Cell. Biochem. Suppl. 16G: 143–150

  • Balczon R, Bao L, Zimmer WE, Brown K, Zinkowski RP, Brinkley BR . 1995 J. Cell. Biol. 130: 105–115

  • Bates S, Hickman ES, Vousden KH . 1999 Mol. Carcinog. 24: 7–14

  • Blair Zajdel ME, Blair GE . 1988 Oncogene 2: 579–584

  • Bornens M . 1992 The Centrosome Kalnins VI (ed) Academic Press: San Diego pp. 2–43

    Google Scholar 

  • Brinkley BR, Goepfert TM . 1998 Cell. Motil. Cytoskelton 41: 281–288

  • Brown CR, Doxsey SJ, White E, Welch WJ . 1994 J. Cell. Physiol. 160: 47–60

  • Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li Y-Q, Tarapore P, Fukasawa K . 1999 Oncogene 18: 1935–1944

  • Chiba S, Okuda M, Mussman JG, Fukasawa K . 2000 Exp. Cell. Res. 258: 310–321

  • Cho Y, Gorina S, Jeffrey PD, Pavletich NP . 1994 Science 265: 346–355

  • Crook T, Vousden KH . 1992 EMBO J. 11: 3935–3940

  • Crook T, Marston NJ, Sara EA, Vousden KH . 1994 Cell 79: 817–827

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CJ, Butel JS, Bradley A . 1992 Nature 356: 215–221

  • Dulic V, Lees E, Reed S . 1992 Science 257: 1958–1961

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Elledge RM, Allred DC . 1998 Breast Cancer Res. Treat. 52: 79–98

  • Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF . 1996 Science 271: 1744–1747

  • Fukasawa K, Wiener F, Vande Woude GF, Mai S . 1997 Oncogene 15: 1295–1302

  • Fuchs B, O'Connor D, Fallis L, Scheidtmann KH, Lu X . 1995 Oncogene 10: 789–793

  • Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H . 1995 Science 268: 1766–1769

  • Gu Y, Turck CW, Morgan DO . 1993 Nature 366: 707–710

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Panayotis P, Giovanella BC, Tainsky MA, Bradley A, Donehower LA . 1993 Oncogene 8: 2457–2467

  • Hinchcliffe EH, Li C, Thompson EA, Maller JL, Sluder G . 1999 Science 283: 851–854

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . 1991 Science 253: 49–53

  • Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA . 1994 Curr. Biol. 4: 1–7

  • Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Konishi M, Kawashima I, Takamoto S, Hirai H, Miyaki M . 1995 Oncogene 11: 1339–1345

  • Ko LJ, Prives C . 1996 Genes Dev. 10: 1054–1072

  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan D, Franza BR, Roberts JM . 1992 Science 257: 1689–1694

  • Lacey KR, Jackson PK, Stearns T . 1999 Proc. Natl. Acad. Sci. USA 96: 2817–2822

  • Lange BM, Faragher AJ, March P, Gull K . 2000 Curr. Top. Dev. Biol. 49: 235–249

  • Levine AJ, Momand J, Finlay CA . 1991 Nature 351: 453–456

  • Liu G, McDonnell TJ, Montes de Oca Luna R, Kapoor M, El-Naggar AK, Lozano G . 2000 Proc. Natl. Acad. Sci. USA 97: 4174–4179

  • Mantel C, Braun SE, Reid S, Henegariu O, Liu L, Hangoc G, Broxmeyer HE . 1999 Blood 93: 1390–1398

  • Matsumoto Y, Hayashi K, Nishida E . 1999 Curr. Biol. 9: 429–432

  • Mazia D . 1987 Int. Rev. Cytology 100: 49–92

  • Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA . 1999 Nature Cell. Biol. 1: 88–93

  • Mowat MRA . 1998 Adv. Cancer Res. 74: 25–48

  • Murphy KL, Dennis AP, Rosen JM . 2000 FASEB J. 14: 2291–2302

  • Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA, Fukasawa K . 2000 Oncogene 19: 1635–1646

  • Nylander K, Dabelsteen E, Hall PA . 2000 J. Oral Pathol. Med. 29: 413–425

  • Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan P-K, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K . 2000 Cell 103: 127–140

  • Ozen H, Hall MC . 2000 Curr. Opin. Oncol. 12: 255–259

  • Price BD, Hughes-Davies L, Park SJ . 1995 Oncogene 11: 73–80

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

  • Sluder G, Hinchcliffe EH . 2000 Curr. Top. Dev. Biol. 49: 251–266

  • Tarapore P, Fukasawa K . 2000 Cancer Invest. 18: 148–155

  • Tarapore P, Horn HF, Tokuyama Y, Fukasawa K . 2001 Oncogene 20: 3173–3184

  • Urbani L, Stearns T . 1999 Curr. Biol. 9: 315–317

  • Vandre DD, Borisy GG . 1989 Mitosis: Molecules and Mechanisms J.S. Hyams and B.R. Brinkley, eds.), Academic Press, San Diego pp. 39–75

    Google Scholar 

  • Vet JA, Debruyne FM, Schalken JA . 1994 World J. Urol. 12: 84–88

  • Wang XJ, Greenhalgh DA, Jiang A, He D, Zhong L, Brinkley BR, Roop DR . 1998 Molec. Carcinog. 23: 185–192

  • Wang Y, Prives C . 1995 Nature 376: 88–91

  • Weber RG, Bridger JM, Benner A, Weisenberger D, Ehemann V, Reifenberger G, Lichter P . 1998 Cytogenet. Cell. Genet. 83: 266–269

  • Williams NN, Daly JM . 1990 Surg. Gynecol. Obstet. 171: 257–266

  • Winey M . 1996 Current Biol. 6: 962–964

  • Wong K-B, DeDecker BS, Freund SMV, Proctor MP, Bycroft M, Fersht AR . 1999 Proc. Natl. Acad. Sci. USA 96: 8438–8442

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . 1993 Nature 366: 701–704

Download references

Acknowledgements

We thank Dr K Vousden for providing us p53 plasmids, and Mr T Kim for technical assistance. This work was supported by Grant CA90522 from the National Institute of Health.

Author information

Authors and Affiliations

  1. Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521, Cincinnati, OH 45267-0521, Ohio, USA

    Pheruza Tarapore, Yukari Tokuyama, Henning F Horn & Kenji Fukasawa

Authors
  1. Pheruza Tarapore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukari Tokuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henning F Horn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Fukasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenji Fukasawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tarapore, P., Tokuyama, Y., Horn, H. et al. Difference in the centrosome duplication regulatory activity among p53 ‘hot spot’ mutants: potential role of Ser 315 phosphorylation-dependent centrosome binding of p53. Oncogene 20, 6851–6863 (2001). https://doi.org/10.1038/sj.onc.1204848

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204848

Keywords

This article is cited by

Search

Advanced search

Quick links