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Papers In Press, published online ahead of print January 4, 2001
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan 20157
Corresponding Author: damia{at}marionegri.it
The levels of the human checkpoint gene hCHK1 were measured in human cancer cells growing in vitro after treatment with the DNA damaging agent cisplatinum (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 mRNA level by using Northern blot analysis. By using isogenic cell systems in which p53 has been disrupted either by transfection with HPV-E6 or by targeted homologous recombination, we found that the DNA damage-induced downregulation of hCHK1 was only observable in wt 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 downregulation of hCHK1 is likely to be at transcriptional levels, as suggested by lack of downregulation of the hCHK1 when transfected under the control of an heterologous viral promoter. In addition, p53 is able to downregulate 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.
J. Biol. Chem, 10.1074/jbc.M007178200
Submitted on August 8, 2000
Revised on January 4, 2001
Accepted on January 3, 2001
DNA damage induces p53-dependent downregulation of hCHK1
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