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DNA Damage-associated Dysregulation of the Cell Cycle and Apoptosis Control in Cells with Germ-line p53 Mutation¹

Department of Virology, The National Children's Meeical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154, Japan [K. G., M. T., S. I., S. M., M. A.]; Division Oncologia Sperimentale, Instituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy [D. D., R. D.]; Department of Hematology, The National Children's Hospital, 3-35-31 Taishido, Setagaya-ku, Tokyo 154, Japan [Y. T.]; Department of Pediatrics, Yamanashi Medical University, 1110 Shimokawahigashi, Tamaho-cho, Nakakuma-Gun, Yamanashi 409-38, Japan [S. N.]; Department of Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku 104, Tokyo, Japan [H. Y.]; Biology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku 104, Tokyo, Japan [J. Y.]; Department of Surgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663, Japan [K. T., Y. S., J. U.]; Laboratory of Chemotherapy, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464, Japan [T. T., R. U.]; Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980, Japan [C. I.]; and Department of Cancer Cytogenetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan [M. E., N. K.]

Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from five independent Li-Fraumeni syndrome families. When cell cycle regulation in response to -irradiation was studied, these LCLs showed an abnormal G₁ checkpoint associated with defective inhibition of cyclin E/cyclindependent kinase 2 activity in all cases except for 282W LCL, which showed a normal G₁ checkpoint. On the other hand, the control of S-phase-G₂ as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G₁ arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G₁-S-phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G₂ and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.

¹ Supported by a grant-in-aid for Pediatric Research 6-5 and a grant-in-aid for cancer research from the Ministry of Health and Welfare, Japan; by a grant-in-aid from the Ministry of Health and Welfare, Japan, as part of a comprehensive 10-year strategy for cancer control; by a grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan; by a grant from the Human Science Foundation, Japan; by a grant from the Japan Leukemia Research Fund; and by the Italian Association for Cancer Research.

² Present address: Department of Pediatrics, Yamanashi Medical University, 1110 Shimokawahigashi, Tamaho-cho, Nakakuma-gun, Yamanashi 409-38, Japan.

³ Present address: The Second Department of Internal Medicine, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ka, Nagoya 467, Japan.

⁴ To whom requests for reprints should be addressed. Phone: 03-3414-8121; Fax: 03-3419-4757; E-mail: smizutani@nch.go.jp.

Received 11/13/96. Accepted 3/24/97.

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