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Science 22 March 1996: Vol. 271. no. 5256, pp. 1744 - 1747 DOI: 10.1126/science.271.5256.1744
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Reports
Abnormal Centrosome Amplification in the Absence of p53
Kenji Fukasawa,
Taesaeng Choi,
Ryoko Kuriyama,
Shen Rulong,
George F. Vande
Woude
*
The centrosome plays a vital role in mitotic fidelity, ensuring
establishment of bipolar spindles and balanced chromosome segregation.
Centrosome duplication occurs only once during the cell cycle and is
therefore highly regulated. Here, it is shown that in mouse embryonic
fibroblasts (MEFs) lacking the p53 tumor suppressor protein, multiple
copies of functionally competent centrosomes are generated during a
single cell cycle. In contrast, MEFs prepared from normal mice or mice
deficient in the retinoblastoma tumor suppressor gene product do not
display these abnormalities. The abnormally amplified centrosomes
profoundly affect mitotic fidelity, resulting in unequal segregation of
chromosomes. These observations implicate p53 in the regulation of
centrosome duplication and suggest one possible mechanism by which the
loss of p53 may cause genetic instability.
K. Fukasawa, T. Choi, S. Rulong, G. F. Vande Woude, ABL-Basic
Research Program, National Cancer Institute, Frederick Cancer Research
and Development Center, Post Office Box B, Frederick, MD 21702-1201,
USA.
R. Kuriyama, Department of Cell Biology and Neuroanatomy, University of
Minnesota Medical School, Minneapolis, MN 55455, USA.
*
To whom correspondence should be adressed.
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- Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1.
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J. Cell Sci.
114, 797-809
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- Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring.
- J. E. Baulch, O. G. Raabe, and L. M. Wiley (2001)
Mutagenesis
16, 17-23
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- Progesterone facilitates chromosome instability (aneuploidy) in p53 null normal mammary epithelial cells.
- T. M. GOEPFERT, M. MCCARTHY, F. S. KITTRELL, C. STEPHENS, R. L. ULLRICH, B. R. BRINKLEY, and D. MEDINA (2000)
FASEB J
14, 2221-2229
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- A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model.
- K. L. MURPHY, A. P. DENNIS, and J. M. ROSEN (2000)
FASEB J
14, 2291-2302
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- Base excision repair is efficient in cells lacking poly(ADP-ribose) polymerase 1.
- M. D. Vodenicharov, F. R. Sallmann, M. S. Satoh, and G. G. Poirier (2000)
Nucleic Acids Res.
28, 3887-3896
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- The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle.
- S. Duensing, L. Y. Lee, A. Duensing, J. Basile, S.-o. Piboonniyom, S. Gonzalez, C. P. Crum, and K. Munger (2000)
PNAS
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- Multicolour FISH detection of radioactive iodine-induced 17cen-p53 chromosomal breakage in buccal cells from therapeutically exposed patients.
- M.J. Ramirez, S. Puerto, P. Galofre, E.M. Parry, J.M. Parry, A. Creus, R. Marcos, and J. Surralles (2000)
Carcinogenesis
21, 1581-1586
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- Genetic and Hormonal Risk Factors in Breast Cancer.
- A.-M. Martin and B. L. Weber (2000)
J Natl Cancer Inst
92, 1126-1135
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- Chromosome instability contributes to loss of heterozygosity in mice lacking p53.
- C. Shao, L. Deng, O. Henegariu, L. Liang, P. J. Stambrook, and J. A. Tischfield (2000)
PNAS
97, 7405-7410
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- Cancer Risk and the ATM Gene: a Continuing Debate.
- K. K. Khanna (2000)
J Natl Cancer Inst
92, 795-802
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- Retinoblastoma Protein Enhances the Fidelity of Chromosome Segregation Mediated by hsHec1p.
- L. Zheng, Y. Chen, D. J. Riley, P.-L. Chen, and W.-H. Lee (2000)
Mol. Cell. Biol.
20, 3529-3537
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- XCS-1, a maternally expressed gene product involved in regulating mitosis in Xenopus.
- H Nakamura, C Wu, J Kuang, C Larabell, and L. Etkin (2000)
J. Cell Sci.
113, 2497-2505
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- Role of DNA Break-sensing Molecule Poly(ADP-ribose) Polymerase (PARP) in Cellular Function and Radiation Toxicity.
- W.-M. TONG, D. GALENDO, and Z.-Q. WANG (2000)
Cold Spring Harb Symp Quant Biol
65, 583-592
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- MAPK Mediates RAS-induced Chromosome Instability.
- H. I. Saavedra, K. Fukasawa, C. W. Conn, and P. J. Stambrook (1999)
J. Biol. Chem.
274, 38083-38090
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- Defects in transforming growth factor-beta signaling cooperate with a Ras oncogene to cause rapid aneuploidy and malignant transformation of mouse keratinocytes.
- A. Glick, N. Popescu, V. Alexander, H. Ueno, E. Bottinger, and S. H. Yuspa (1999)
PNAS
96, 14949-14954
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- Altered Centrosome Structure Is Associated with Abnormal Mitoses in Human Breast Tumors.
- W. L. Lingle and J. L. Salisbury (1999)
Am. J. Pathol.
155, 1941-1951
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- Chromosomal aberrations in PARP-/- mice: Genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA.
- C. M. Simbulan-Rosenthal, B. R. Haddad, D. S. Rosenthal, Z. Weaver, A. Coleman, R. Luo, H. M. Young, Z.-Q. Wang, T. Ried, and M. E. Smulson (1999)
PNAS
96, 13191-13196
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- Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.
- C. M. Eischen, J. D. Weber, M. F. Roussel, C. J. Sherr, and J. L. Cleveland (1999)
Genes & Dev.
13, 2658-2669
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- Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle.
- E. Freed, K. R. Lacey, P. Huie, S. A. Lyapina, R. J. Deshaies, T. Stearns, and P. K. Jackson (1999)
Genes & Dev.
13, 2242-2257
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- How many tumor suppressor genes are involved in human lung carcinogenesis?.
- T. Kohno and J. Yokota1 (1999)
Carcinogenesis
20, 1403-1410
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- Apoptotic and Mitotic Indices Predict Survival Rates in Lymph Node-negative Colon Carcinomas.
- F. A. Sinicrope, J. Hart, H.-A. Hsu, M. Lemoine, F. Michelassi, and L. C. Stephens (1999)
Clin. Cancer Res.
5, 1793-1804
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- Budding Yeast Bub2 Is Localized at Spindle Pole Bodies and Activates the Mitotic Checkpoint via a Different Pathway from Mad2.
- R. Fraschini, E. Formenti, G. Lucchini, and S. Piatti (1999)
J. Cell Biol.
145, 979-991
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- Centrosome Abnormalities in Pancreatic Ductal Carcinoma.
- N. Sato, K. Mizumoto, M. Nakamura, K. Nakamura, M. Kusumoto, H. Niiyama, T. Ogawa, and M. Tanaka (1999)
Clin. Cancer Res.
5, 963-970
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- Roles of the functional loss of p53 and other genes inastrocytoma tumorigenesis and progression.
- M. Nozaki, M. Tada, H. Kobayashi, C.-L. Zhang, Y. Sawamura, H. Abe, N. Ishii, and E. G. Van Meir (1999)
Neuro Oncology
1, 124-137
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