Abstract
Centrosome hyperamplification and the consequential mitotic defects contribute to chromosome instability in cancers. Loss or mutational inactivation of p53 has been shown to induce chromosome instability through centrosome hyperamplification. It has recently been found that Cdk2-cyclin E is involved in the initiation of centrosome duplication, and that constitutive activation of Cdk2-cyclin E results in the uncoupling of the centrosome duplication cycle and the DNA replication cycle. Cyclin E overexpression and p53 mutations occur frequently in tumors. Here, we show that cyclin E overexpression and loss of p53 synergistically increase the frequency of centrosome hyperamplification in cultured cells as well as in tumors developed in p53-null, heterozygous, and wild-type mice. Through examination of cells derived from Waf1-null mice, we further found that Waf1, a potent inhibitor of Cdk2-cyclin E and a major target of p53's transactivation function, is involved in coordinating the initiation of centrosome duplication and DNA replication, suggesting that Waf1 may act as a molecular link between p53 and Cdk2-cyclin E in the control 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
Bornens M . 1992 The Centrosome Kalnins VI ed New York Academic Press pp 1–43
Brinkley BR . 1985 Ann Rev Cell Biol 1: 145–172
Carbonaro-Hall D, Williams R, Wu L, Warburton D, Zeichner-David M, MacDougall M, Tolo V and Hall F . 1993 Oncogene 9: 71–79
Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li Y-Q, Tarapore P and Fukasawa K . 1999 Oncogene 18: 1935–1944
Cheng M, Oliver P, Diehl JA, Fero M, Roussel MF, Roberts JM and Sherr CJ . 1999 EMBO J 18: 1571–1583
Deng C, Zhang P, Harper JW, Elledge SJ and Leder P . 1995 Cell 82: 675–684
Dulic V, Lees E and 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 and Vogelstein B . 1993 Cell 75: 817–825
Fukasawa K, Murakami M, Blai D, Kuriyama R, Hunt T and Vande Woude GF . 1994 Cell Growth Diff 5: 1093–1103
Fukasawa K, Choi T, Kuriyama R, Rulong S and Vande Woude GF . 1996 Science 271: 1744–1747
Fukasawa K, Wiener F, Vande Woude GF and Mai S . 1997 Oncogene 15: 1295–1302
Fukasawa K and Vande Woude GF . 1997 Mol Cell Biol 17: 506–518
Gannon JV, Greaves R, Iggo R and Lane DP . 1990 EMBO J 9: 1595–1602
Girard F, Strausfeld U, Fernandez A and Lamb NJ . 1991 Cell 67: 1169–1179
Gu Y, Turck CW and Morgan DO . 1993 Nature 366: 707–710
Harlow E and Lane D . 1998 Antibodies a laboratory manual p380, Cold Spring Harbor Laboratory Press
Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ . 1993 Cell 75: 805–816
Harvey DM and Levine AJ . 1991 Genes Dev 5: 2375–2385
Haupt Y, Kazaz A and Oren M . 1997 Nature 387: 296–299
Heichman KA and Roberts JM . 1994 Cell 79: 557–562
Hickman ES, Bates S and Vousden KH . 1997 J Virol 71: 3710–3718
Hinchcliffe EH, Li C, Thompson EA, Maller JL and 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, Fern'andez-Salguero PM, Morgan WF, Deng CX and Fornace Jr AJ . 1999 Nat Genet 23: 176–184
Hollstein M, Sidransky D, Vogelstein B and Harris CC . 1991 Science 253: 49–53
Hsu LC and White RL . 1998 Proc Natl Acad Sci USA 95: 12983–12988
Iggo R, Gatter K, Bartek J, Lane D and Harris AL . 1990 Lancet 335: 675–679
Joshi HC, Monica JP, McNamara L and Cleveland DW . 1992 Nature 356: 80–83
Keyomarsi K and Herliczek TW . 1997 Prog Cell Cycle Res 3: 171–191
Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan D, Franza BR and Roberts JM . 1992 Science 257: 1689–1694
Kubbutat MH, Jones SN and Vousden K . 1997 Nature 387: 299–303
LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A and Harlow E . 1997 Genes Dev 11: 847–862
Lacey KR, Jackson PK and Stearns T . 1999 Proc Natl Acad Sci USA 96: 2817–2822
Lange BM and Gull K . 1996 Trends Cell Biol 6: 348–352
Levine AJ, Momand J and Finlay CA . 1991 Nature 351: 453–456
Marraccino RL, Firpo EJ and Roberts JM . 1992 Mol Biol Cell 3: 389–401
Martinez J, Georgoff I, Martinez J and Levine AJ . 1991 Genes Dev 5: 151–159
Matsumoto T, Hayashi K and Nishida E . 1999 Curr Biol 9: 429–432
Mazia D . 1987 Int Rev Cytology 100: 49–92
Meraldi P, Lukas J, Fry A, Bartek J and Nigg EA . 1999 Nature Cell Biol 1: 88–93
Momand J, Zambetti GP, Olson DC, George D and Levine AJ . 1992 Cell 69: 1237–1245
Momand J and Zambetti G . 1997 J Cell Biochem 64: 343–352
Morgan DO . 1997 Annu Rev Cell Dev Biol 13: 261–291
Niculescu III AB, Chen X, Smeet M, Hengst L, Prives C and Reed SI . 1998 Mol Cell Biol 18: 629–643
Nowell PC . 1976 Science 194: 23–28
Nurse P . 1994 Cell 79: 547–550
Ohtsubo M and Roberts JM . 1993 Science 259: 1908–1912
Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM and Pagano M . 1995 Mol Cell Biol 15: 2612–2624
Oliner JD, Kinzler KW, Meltzer PS, George D and Vogelstein B . 1992 Nature 358: 80–83
Oliner JD, Pietenpol JA, Thiagallngam S, Gyuris J, Kinzler KW and Vogelstein B . 1993 Nature 362: 857–860
Pagano M, Pepperkok R, Verde F, Ansorge W and Draetta G . 1992 EMBO J 11: 961–971
Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P and Doxsey SJ . 1998 Cancer Res 58: 3974–3985
Reed SI . 1997 Cancer Surv 29: 7–23
Resnitzky D, Gossen M, Bujard H and Reed SI . 1994 Mol Cell Biol 14: 1669–1679
Rittling SR and Denhardt DT . 1992 Oncogene 7: 935–942
Sgambato A, Doki Y, Scheren I and Weinstein IB . 1997 Cell Growth Diff 8: 393–405
Sherr CH . 1994 Cell 79: 551–555
Sherr CH and Roberts JM . 1995 Genes Dev 9: 1149–1163
Spruck CH, Won K-A and Reed SI . 1999 Nature 401: 297–300
Stearns T, Evans L and Kirschner M . 1991 Cell 65: 825–836
Stillman B . 1996 Science 274: 1659–1664
Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H and Okano Y . 1999 Cancer Res 59: 2041–2044
Todaro GJ and Green H . 1963 J Cell Biol 17: 299–313
Tournier F and Bornens M . 1994 Microtubules Hyams JS and Lloyd CW eds Wiley-Liss New York pp 303–324
van der Heuvel S and Harlow E . 1993 Science 262: 2050–2054
Vandre DD and Borisy GG . 1989 Mitosis Molecules and Mechanisms Hyams JS and Brinkley BR eds San Diego Academic Press pp 39–75
Venkatachalam S, Shi Y-P, Jones NJ, Vogel H, Bradley A, Pinkel D and Donehower LA . 1998 EMBO J 17: 4657–4667
Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, O'Connor PM, Fornace Jr AJ and Harris CC . 1999 Proc Natl Acad Sci USA 96: 3706–3711
Weber RG, Bridger JM, Benner A, Weisenberger D, Ehemann V, Reifenberger G and Lichter P . 1998 Cytogen Cell Gen 83: 266–269
Wimmel A, Lucibello FC, Sewing A, Adolph S and Muller R . 1994 Oncogene 9: 995–997
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D . 1993 Nature 366: 701–704
Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T and Deng CX . 1999 Mol Cell 3: 389–395
Yewdell JW, Gannon JV and Lane DP . 1986 J Virol 59: 444–452
Zhang H, Hannon GJ and Beach D . 1994 Genes Dev 8: 1750–1758
Zheng Y, Jung MK and Oakley BR . 1991 Cell 65: 817–823
Zhou H, Kuang J, Zhong L, Kuo W, Gray JW, Sahin A, Brinkley BR and Sen S . 1998 Nature Genet 20: 189–193
Acknowledgements
We thank Dr Philip Leder for Waf1−/− and Waf1+/+ MEFs, Dr Fred Mushinski for the mouse Waf1 cDNA, and Dr George Babcock and Mr Jim Cornelius for flow cytometric analysis. We also thank T Kim, T Hagerty and A Dierkers for technical assistance. We also thank Mr S Tyner for organizing and preparing the tumor samples. This work was supported in part by grants from American Cancer Society, and Cancer Research Challenge and Ruth Lyons Fund.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mussman, J., Horn, H., Carroll, P. et al. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression. Oncogene 19, 1635–1646 (2000). https://doi.org/10.1038/sj.onc.1203460
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203460
Keywords
This article is cited by
-
Geometric network analysis provides prognostic information in patients with high grade serous carcinoma of the ovary treated with immune checkpoint inhibitors
npj Genomic Medicine (2021)
-
Centrosomes in the DNA damage response—the hub outside the centre
Chromosome Research (2016)
-
Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts
Molecular Cancer (2013)
-
Such small hands: the roles of centrins/caltractins in the centriole and in genome maintenance
Cellular and Molecular Life Sciences (2012)
-
Aberrant Activation of Cell Cycle Regulators, Centrosome Amplification, and Mitotic Defects
Hormones and Cancer (2011)