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Molecular and Cellular Biology, April 1999, p. 2828-2834, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Requirement of ATM in Phosphorylation of the Human p53 Protein at Serine 15 following DNA Double-Strand Breaks

Kazumi Nakagawa,1 Yoichi Taya,2 Katsuyuki Tamai,3 and Masaru Yamaizumi1,*

Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 862-0976,1 National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045,2 and Ina Laboratory, MBL Co. Ltd., Ina, Nagano 396,3 Japan

Received 17 September 1998/Returned for modification 3 November 1998/Accepted 7 January 1999

Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.

* Corresponding author. Mailing address: Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kuhonji 4-24-1, Kumamoto 862-0976, Japan. Phone: 81(96)373-5340. Fax: 81(96)364-3554. E-mail: yamaizm{at}gpo.kumamoto-u.ac.jp.

Molecular and Cellular Biology, April 1999, p. 2828-2834, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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