Abstract
The function of the centrosomes to direct mitotic spindles is critical for accurate chromosome transmission to daughter cells. Since each daughter cell inherits one centrosome, each centrosome must duplicate prior to the next mitosis, and do so only once. Thus, there are control mechanism(s) that ensure the coordinated progression of centrosome duplication and other cell cycle events (i.e. DNA synthesis), and limit centrosome duplication to once per cell cycle. Deregulation of the centrosome duplication cycle results in abnormal amplification of centrosomes, leading to aberrant mitoses and increased chromosome transmission errors. This has been found to be the case for cells lacking functional p53 tumor suppressor protein. However, it had remained to be determined whether the deregulation of the centrosome duplication cycle is the direct or indirect effect of loss/mutational inactivation of p53. Here, we found that the normal centrosome duplication cycle is almost completely restored in p53−/− cells by re-introduction of wild-type p53 at a physiologically relevant level, demonstrating that p53 is directly involved in the regulation of centrosome duplication. Since cyclin dependent kinase 2 (CDK2)/cyclin E triggers DNA synthesis as well as centrosome duplication, we tested whether Waf1, a CDK inhibitor and a major target of p53's transactivation function, is an effector of p53-mediated regulation of centrosome duplication. We found that induced expression of Waf1 in p53−/− cells only partially restored the centrosome duplication control, suggesting that Waf1 comprises one of the multiple effector pathways of the p53-mediated regulation of the centrosome duplication cycle.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Balczon R, Bao L, Zimmer WE, Brown K, Zinkowski RP, Brinkley BR . 1995 J. Cell Biol. 130: 105–115
Bornens M . 1992 The Centrosome VI Kalnins. (ed) Academic Press: New York pp. 1–43
Brinkley BR . 1985 Ann. Rev. Cell Biol. 1: 145–172
Brinkley BR, Gæpfert TM . 1998 Cell Motil. Cytoskeleton 41: 281–288
Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li Y-Q, Tarapore P, Fukasawa K . 1999 Oncogene 18: 1935–1944
Chen S, Blanck G, Pollack RE . 1983 Proc. Natl. Acad. Sci. USA 80: 5670–5674
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
Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF . 1996 Science 271: 1744–1847
Fukasawa K, Wiener F, Vande Woude GF, Mai S . 1997 Oncogene 15: 1295–1302
Fukasawa K, Vande Woude GF . 1997 Mol. Cell. Biol. 17: 506–518
Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H . 1995 Science 268: 1766–1769
Gottlieb MT, Oren M . 1996 Biochem. Biophys. Acta. 1287: 77–102
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
Heichman KA, Roberts JM . 1994 Cell 79: 557–562
Hinchcliffe EH, Li C, Thompson EA, Maller JL, Sluder G . 1999 Science 283: 851–854
Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ . 1999 Nat. Genet. 23: 176–184
Hollstein M, Sidransky D, Vogelstein B, Harris CC . 1991 Science 253: 49–53
Hu T, Miller CM, Ridder GM, Aardema MJ . 1999 Mutat. Res. 426: 51–62
Joshi HC . 1994 Curr. Opin. Cell Biol. 6: 54–62
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, Gull K . 1996 Trends Cell Biol. 6: 348–352
Lee H, Larner JM, Hamlin JL . 1997 Gene 184: 177–183
Levine AJ, Momand J, Finlay CA . 1991 Nature 351: 453–456
Lingle WL, Lutz WH, Ingle JN, Maihle NJ, Salisbury JL . 1998 Proc. Natl. Acad. Sci. USA 95: 2950–2955
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
Moro F, Ottaggio L, Bonatti S, Simili S, Miele M, Bozzo S, Abbondandolo A . 1995 Carcinogenesis 16: 2435–2440
Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA, Fukasawa K . 2000 Oncogene 19: 1635–1646
Nurse P . 1994 Cell 79: 547–550
Ohtsubo M, Roberts JM . 1993 Science 259: 1908–1912
Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M . 1995 Mol. Cell. Biol. 15: 2612–2624
Ouchi T, Montero AN, August A, Aaronson SA, Hanafusa H . 1998 Proc. Natl. Acad. Sci. USA 95: 2302–2306
Pihan GA, Purohit A, Wallace J, Knecht H, Woda BH, Quesenberry P, Doxsey SJ . 1998 Cancer Res. 58: 3974–3985
Resnitzky D, Gossen M, Bujard H, Reed SI . 1994 Mol. Cell. Biol. 14: 1669–1679
Sherr CH . 1994 Cell 79: 551–555
Sherr CH, Roberts JM . 1999 Genes Dev. 13: 1501–1512
Somasundaram K, Zhang H, Zeng Y-X, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS . 1997 Nature 389: 187–190
Tournier F, Bornens M . 1994 Microtubules JS Hyams and CW Lloyd. (eds) Wiley-Liss: New York pp. 303–324
van den Heuvel S, Harlow E . 1993 Science 262: 2050–2054
Vandre DD, Borisy GG . 1989 Mitosis: Molecules and Mechanisms JS Hyams and BR Brinkley. (eds) Academic Press: San Diego pp. 39–75
Wang XJ, Greenhalgh DA, Jiang A, He D, Zhong L, Brinkley BR, Roop DR . 1998 Mol. Carcinog. 23: 185–192
Wahl GM, Linke SP, Paulson TG, Huang LC . 1997 Cancer Sur. 29: 183–219
Weber RG, Bridger JM, Brenner A, Weisenberger D, Ehemann V, Reifenberger G, Lichter P . 1998 Cytogen. Cell Gen. 83: 266–269
Winey M . 1996 Curr. Biol. 6: 962–964
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . 1993 Nature 366: 701–704
Xu X, Weaver Z, Linke SP, Li C, Gottay J, Wang X-W, Harris CC, Ried T, Deng C-X . 1999 Mol. Cell. 3: 389–395
Acknowledgements
We thank Drs F Mushinski for the mouse Waf1 cDNA, J Roberts for cylcin E plasmids, L Donehower for p53+/+ and p53−/− MEFs, and P Leder for Waf1−/− and Waf1+/+ MEFs, as well as Drs G Babcock and J Cornelius for flow cytometric analysis. We also thank T Kim and T Hagarty for technical assistance. This research is supported in part by Ruth Lyons Fund.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tarapore, P., Horn, H., Tokuyama, Y. et al. Direct regulation of the centrosome duplication cycle by the p53-p21Waf1/Cip1 pathway. Oncogene 20, 3173–3184 (2001). https://doi.org/10.1038/sj.onc.1204424
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204424