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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 Damia^§, Yolanda Sanchez^¶, Eugenio Erba, and Massimo Broggini

From the  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.

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