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Molecular and Cellular Biology, November 2003, p. 8161-8171, Vol. 23, No. 22
0270-7306/03/$08.00+0 DOI: 10.1128/MCB.23.22.8161-8171.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
p73
Regulation by Chk1 in Response to DNA Damage
Susana Gonzalez,1 Carol Prives,2 and Carlos Cordon-Cardo1*
Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,1
Department of Biological Sciences, Columbia University, New York, New York 100272
Received 1 April 2003/
Returned for modification 5 June 2003/
Accepted 6 August 2003
The checkpoint kinase 1 (Chk1) is an essential component of the DNA damage checkpoint. Previous studies have demonstrated an indispensable role for the p53-related transcription factor p73
in DNA damage-induced apoptosis. Here, we provide evidence that p73
is a target of Chk1. We found that endogenous p73
is serine phosphorylated by endogenous Chk1 upon DNA damage, which is a mechanism required for the apoptotic-inducing function of p73
. Consistent with this, we discovered that endogenous p73
interacts with Chk1 and is phosphorylated by Chk1 at serine 47 in vitro and in vivo. In contrast, Chk2 does not phosphorylate p73
in vitro. Moreover, mutation of serine 47 abolishes both Chk1-dependent phosphorylation of p73
upon DNA damage in vivo and the ability of Chk1 to upregulate the transactivation capacity of p73
. Our data indicate a novel biochemical pathway through which the p73
proapoptotic function requires DNA damage-triggered p73
phosphorylation by Chk1.
* Corresponding author. Mailing address: Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. Phone: (212) 639-7746. Fax: (212) 794-3286. E-mail:
cordon-c{at}mskcc.org.
Molecular and Cellular Biology, November 2003, p. 8161-8171, Vol. 23, No. 22
0022-538X/03/$08.00+0 DOI: 10.1128/MCB.23.22.8161-8171.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
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