DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2-Reference-Cited by-同舟云学术

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

Published:2000-03-10 Issue:5459 Volume:287 Page:1824-1827
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Hirao Atsushi¹,Kong Young-Yun¹,Matsuoka Shuhei²,Wakeham Andrew¹,Ruland Jürgen¹,Yoshida Hiroki¹,Liu Dou²,Elledge Stephen J.²,Mak Tak W.¹

Affiliation:

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.

Abstract

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 γ-irradiation–induced arrest in the G 2 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 γ irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to γ 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference32 articles.

1. Cell Cycle Checkpoints: Preventing an Identity Crisis

2. Linkage of ATM to Cell Cycle Regulation by the Chk2 Protein Kinase

3. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase

4. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

5. An 11-kb genomic Chk2 fragment was isolated from a mouse genomic 129/J library. A 5-kb sequence containing exons encoding the kinase domain of Chk2 was replaced by a neomycin cassette inserted in the antisense orientation. E14K ES cells were electroporated with the linearized construct and G418-resistant ES colonies were identified by polymerase chain reaction and Southern blotting. Chk2 −/− ES cell lines were generated by culturing G418-resistant Chk2 +/ − ES clones in G418 (3.6 mg/ml; Gibco).

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