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Science 10 March 2000:
Vol. 287. no. 5459, pp. 1824 - 1827
DOI: 10.1126/science.287.5459.1824
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Reports

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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   Abstract »    Full Text »    PDF »
ATM-Mediated Stabilization of hMutL DNA Mismatch Repair Proteins Augments p53 Activation during DNA Damage.
Y. Luo, F.-T. Lin, and W.-C. Lin (2004)
Mol. Cell. Biol. 24, 6430-6444
   Abstract »    Full Text »    PDF »
The E4F Protein Is Required for Mitotic Progression during Embryonic Cell Cycles.
L. Le Cam, M. Lacroix, M. A. Ciemerych, C. Sardet, and P. Sicinski (2004)
Mol. Cell. Biol. 24, 6467-6475
   Abstract »    Full Text »    PDF »
Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line.
C. Wicky, A. Alpi, M. Passannante, A. Rose, A. Gartner, and F. Muller (2004)
Mol. Cell. Biol. 24, 5016-5027
   Abstract »    Full Text »    PDF »
Collaboration of Brca1 and Chk2 in tumorigenesis.
J. P. McPherson, B. Lemmers, A. Hirao, A. Hakem, J. Abraham, E. Migon, E. Matysiak-Zablocki, L. Tamblyn, O. Sanchez-Sweatman, R. Khokha, et al. (2004)
Genes & Dev. 18, 1144-1153
   Abstract »    Full Text »    PDF »
Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms.
W. Y. Siu, A. Lau, T. Arooz, J. P.H. Chow, H. T.B. Ho, and R. Y.C. Poon (2004)
Mol. Cancer Ther. 3, 621-632
   Abstract »    Full Text »    PDF »
DNA-dependent Protein Kinase and Checkpoint Kinase 2 Synergistically Activate a Latent Population of p53 upon DNA Damage.
M. T. Jack, R. A. Woo, N. Motoyama, H. Takai, and P. W. K. Lee (2004)
J. Biol. Chem. 279, 15269-15273
   Abstract »    Full Text »    PDF »
Apoptosis Associated with Deregulated E2F Activity Is Dependent on E2F1 and Atm/Nbs1/Chk2.
H. A. Rogoff, M. T. Pickering, F. M. Frame, M. E. Debatis, Y. Sanchez, S. Jones, and T. F. Kowalik (2004)
Mol. Cell. Biol. 24, 2968-2977
   Abstract »    Full Text »    PDF »
E2F1 Uses the ATM Signaling Pathway to Induce p53 and Chk2 Phosphorylation and Apoptosis.
J. T. Powers, S. Hong, C. N. Mayhew, P. M. Rogers, E. S. Knudsen, and D. G. Johnson (2004)
Mol. Cancer Res. 2, 203-214
   Abstract »    Full Text »    PDF »
G2 checkpoint abrogators as anticancer drugs.
T. Kawabe (2004)
Mol. Cancer Ther. 3, 513-519
   Abstract »    Full Text »    PDF »
p53 N-Terminal Ser-15~P and Ser-20~P Levels in Squamous Cell Lung Cancer after Radio/Chemotherapy.
R. M. Mroz, A. Holownia, E. Chyczewska, L. Chyczewski, and J. J. Braszko (2004)
Am. J. Respir. Cell Mol. Biol. 30, 564-568
   Abstract »    Full Text »    PDF »
Recent Advances in Stress Signaling in Cancer.
C. I. Morin and J. Huot (2004)
Cancer Res. 64, 1893-1898
   Abstract »    Full Text »    PDF »
Survivin Loss in Thymocytes Triggers p53-mediated Growth Arrest and p53-independent Cell Death.
H. Okada, C. Bakal, A. Shahinian, A. Elia, A. Wakeham, W.-K. Suh, G. S. Duncan, M. Ciofani, R. Rottapel, J. C. Zuniga-Pflucker, et al. (2004)
J. Exp. Med. 199, 399-410
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice.
H. K. Sluss, H. Armata, J. Gallant, and S. N. Jones (2004)
Mol. Cell. Biol. 24, 976-984
   Abstract »    Full Text »    PDF »
Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage.
M. H. Brodsky, B. T. Weinert, G. Tsang, Y. S. Rong, N. M. McGinnis, K. G. Golic, D. C. Rio, and G. M. Rubin (2004)
Mol. Cell. Biol. 24, 1219-1231
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3{beta}.
L. Qu, S. Huang, D. Baltzis, A.-M. Rivas-Estilla, O. Pluquet, M. Hatzoglou, C. Koumenis, Y. Taya, A. Yoshimura, and A. E. Koromilas (2004)
Genes & Dev. 18, 261-277
   Abstract »    Full Text »    PDF »
Stress-induced Premature Senescence in hTERT-expressing Ataxia Telangiectasia Fibroblasts.
K. Naka, A. Tachibana, K. Ikeda, and N. Motoyama (2004)
J. Biol. Chem. 279, 2030-2037
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Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease.
M. Takagi, R. Tsuchida, K. Oguchi, T. Shigeta, S. Nakada, K. Shimizu, M. Ohki, D. Delia, L. Chessa, Y. Taya, et al. (2004)
Blood 103, 283-290
   Abstract »    Full Text »    PDF »
Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.
M. Lomonosov, S. Anand, M. Sangrithi, R. Davies, and A. R. Venkitaraman (2003)
Genes & Dev. 17, 3017-3022
   Abstract »    Full Text »    PDF »


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