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Originally published In Press as doi:10.1074/jbc.M007178200 on January 4, 2001

J. Biol. Chem., Vol. 276, Issue 14, 10641-10645, April 6, 2001
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DNA Damage Induces p53-dependent Down-regulation of hCHK1*

Giovanna DamiaDagger §, Yolanda Sanchez, Eugenio ErbaDagger , and Massimo BrogginiDagger

From the Dagger  Molecular Pharmacology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy and the  Department of Molecular Genetics, University of Cincinnati MSB 3005, Cincinnati, Ohio 45267

The levels of the human checkpoint gene hCHK1 were measured in human cancer cells growing in vitro after treatment with the DNA damaging agent cis-dichlorodiammine platinum(II) (DDP). Treatment of human cancer cell lines with DDP induced a decrease in the hCHK1 protein levels starting 6 h after treatment, with a further decline at 24 and 48 h. A similar decrease in the levels of hCHK1 was found at the mRNA level by using Northern blot analysis. By using isogenic cell systems in which p53 was disrupted either by transfection with HPV-E6 or by targeted homologous recombination, we found that the DNA damage-induced down-regulation of hCHK1 was only observable in wild type p53-expressing cells, with only a minor decline in the hCHK1 levels observable 48 h after treatment in cells with disrupted p53. Similarly, treatment of mutant p53-expressing human cancer cell lines with DDP did not result in changes in the levels of hCHK1. The p53-dependent down-regulation of hCHK1 is likely to be at transcriptional levels, as suggested by the lack of down-regulation of the hCHK1 when transfected under the control of a heterologous viral promoter. In addition, p53 is able to down-regulate the luciferase activity under the control of the 5' flanking region of the hCHK1 gene. The data suggest a strict link between p53 and hCHK1 governing the activation and repression of the G2 checkpoint in which both proteins participate.


* This work was partially supported by Project Number ICS120/RF98/73 of the Italian Ministry of Health. The generous contributions of the Italian Association for Cancer Research are gratefully acknowledged.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence and requests for reprints should be addressed. Fax: 39-2-3546277; E-mail: damia@irfmn.mnegri.it.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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