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Science 287 (5459): 1824-1827

Copyright © 2000 by the American Association for the Advancement of Science

DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2

Atsushi Hirao, 1 Young-Yun Kong, 1 Shuhei Matsuoka, 2 Andrew Wakeham, 1 Jürgen Ruland, 1 Hiroki Yoshida, 1* Dou Liu, 2 Stephen J. Elledge, 2 Tak W. Mak 1dagger

Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2-/- embryonic stem cells failed to maintain gamma -irradiation-induced arrest in the G2 phase of the cell cycle. Chk2-/- thymocytes were resistant to DNA damage-induced apoptosis. Chk2-/- cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to gamma  irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma  irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. This provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.

1 The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario, M5G 2C1, Canada.
2 Howard Hughes Medical Institute, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, and Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
*   Present address: Department of Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.

dagger    To whom correspondence should be addressed. E-mail: tmak{at}oci.utoronto.ca



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Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant.
E. L. Kwak, S. Kim, J. Zhang, R. D. Cardiff, E. V. Schmidt, and D. A. Haber (2006)
Cancer Res. 66, 1923-1928
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Stalled Replication Induces p53 Accumulation through Distinct Mechanisms from DNA Damage Checkpoint Pathways.
C. C. Ho, W. Y. Siu, A. Lau, W. M. Chan, T. Arooz, and R. Y.C. Poon (2006)
Cancer Res. 66, 2233-2241
   Abstract »    Full Text »    PDF »
The CHEK2*1100delC Allelic Variant and Risk of Breast Cancer: Screening Results from the Breast Cancer Family Registry..
J. L. Bernstein, S. N. Teraoka, E. M. John, I. L. Andrulis, J. A. Knight, R. Lapinski, E. R. Olson, A. L. Wolitzer, D. Seminara, A. S. Whittemore, et al. (2006)
Cancer Epidemiol. Biomarkers Prev. 15, 348-352
   Abstract »    Full Text »    PDF »
Involvement of the ATR- and ATM-Dependent Checkpoint Responses in Cell Cycle Arrest Evoked by Pierisin-1.
B. Shiotani, M. Kobayashi, M. Watanabe, K.-i. Yamamoto, T. Sugimura, and K. Wakabayashi (2006)
Mol. Cancer Res. 4, 125-133
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ATM promotes apoptosis and suppresses tumorigenesis in response to Myc.
R. V. Pusapati, R. J. Rounbehler, S. Hong, J. T. Powers, M. Yan, K. Kiguchi, M. J. McArthur, P. K. Wong, and D. G. Johnson (2006)
PNAS 103, 1446-1451
   Abstract »    Full Text »    PDF »
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(2006)
Experimental Biology and Medicine 231, 91-98
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DNA damage checkpoints in mammals.
H. Niida and M. Nakanishi (2006)
Mutagenesis 21, 3-9
   Abstract »    Full Text »    PDF »
Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated-Dependent Manner.
S. L. Gibson, R. S. Bindra, and P. M. Glazer (2005)
Cancer Res. 65, 10734-10741
   Abstract »    Full Text »    PDF »
WAVE3 Functions as a Negative Regulator of LDOC1.
K. Mizutani, D. Koike, S. Suetsugu, and T. Takenawa (2005)
J. Biochem. 138, 639-646
   Abstract »    Full Text »    PDF »
p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2.
C.-M. Aliouat-Denis, N. Dendouga, I. Van den Wyngaert, H. Goehlmann, U. Steller, I. van de Weyer, N. Van Slycken, L. Andries, S. Kass, W. Luyten, et al. (2005)
Mol. Cancer Res. 3, 627-634
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Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation.
J. Turner, C. Koumenis, T. E. Kute, R. P. Planalp, M. W. Brechbiel, D. Beardsley, B. Cody, K. D. Brown, F. M. Torti, and S. V. Torti (2005)
Blood 106, 3191-3199
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3-Dependent Phosphorylation of Mdm2 Regulates p53 Abundance.
R. Kulikov, K. A. Boehme, and C. Blattner (2005)
Mol. Cell. Biol. 25, 7170-7180
   Abstract »    Full Text »    PDF »
Dual Induction of Apoptosis and Senescence in Cancer Cells by Chk2 Activation: Checkpoint Activation as a Strategy against Cancer.
C.-R. Chen, W. Wang, H. A. Rogoff, X. Li, W. Mang, and C. J. Li (2005)
Cancer Res. 65, 6017-6021
   Abstract »    Full Text »    PDF »

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