DNA damage-induced activation of p53 by the checkp...[Science. 2000]

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1: Science. 2000 Mar 10;287(5459):1824-7. Links

Comment in:: Science. 2000 Mar 10;287(5459):1765-6.

DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW.

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.

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.

PMID: 10710310 [PubMed - indexed for MEDLINE]

Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding.
Mol Cell Biol. 2003 Mar; 23(6):2171-81.

[Mol Cell Biol. 2003]
Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.
Genes Dev. 2000 Feb 1; 14(3):278-88.

[Genes Dev. 2000]
Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner.
Mol Cell Biol. 2002 Sep; 22(18):6521-32.

[Mol Cell Biol. 2002]
ReviewHow to activate p53.
Curr Biol. 2000 Apr 20; 10(8):R315-7.

[Curr Biol. 2000]
ReviewRegulation of p53 in response to DNA damage.
Oncogene. 1999 Dec 13; 18(53):7644-55.

[Oncogene. 1999]
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