This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shigeta, T. Articles by Mizutani, S. Search for Related Content PubMed PubMed Citation Articles by Shigeta, T. Articles by Mizutani, S.

Defective Control of Apoptosis and Mitotic Spindle Checkpoint in Heterozygous Carriers of ATM Mutations¹

Department of Virology, The National Children’s Medical Research Center, Tokyo 154, Japan [T. S., M. T., S. I., M. A., S. M.]; Division of Experimental Oncology Istituto Nazionale Tumori, 20133 Milan, Italy [D. D.]; Department of Experimental Medicine and Pathology, University "La Sapienza," 00161 Rome, Italy [L. C.]; Department of Nutrition, Tokyo University of Agriculture, Tokyo 113, Japan [T. S., Y. K.]; and Department of Cancer Cytogenetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734, Japan [M. E.]

Ataxia telangiectasia (AT) carrier-derived lymphoblastoid cell lines (AT-LCLs/hetero) with suboptimal ATM protein expression were examined for the regulation of radiosensitivity, apoptosis, and mitotic spindle checkpoint in response to DNA-damaging agents. Although AT-LCLs/hetero showed intermediate radiation sensitivity, as determined by clonogenic assay, they were resistant to early-onset apoptosis, as much as AT patient-derived LCLs (AT-LCLs/homo). Furthermore, two of three AT-LCLs/hetero showed defective mitotic spindle checkpoint control in response to X-ray irradiation, which is a recently characterized biological feature in AT-LCLs/homo. Our findings indicate that carriers of ATM mutation have biological abnormalities due to haploinsufficiency of ATM protein or dominant-negative effect of mutant ATM protein. Thus, although it is still controversial whether ATM mutation carriers are at higher risk for cancer during adulthood, our findings based on in vitro biological indicators support the notion that at least some of such carriers are at a higher risk for cancer development than those without ATM mutation. Our findings may help to reevaluate epidemiological studies on cancer susceptibility in AT carriers.

This article has been cited by other articles:

				M. Takagi, R. Tsuchida, K. Oguchi, T. Shigeta, S. Nakada, K. Shimizu, M. Ohki, D. Delia, L. Chessa, Y. Taya, et al. Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease Blood, January 1, 2004; 103(1): 283 - 290. [Abstract] [Full Text] [PDF]

				B. V. Worgul, L. Smilenov, D. J. Brenner, A. Junk, W. Zhou, and E. J. Hall Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts PNAS, July 23, 2002; 99(15): 9836 - 9839. [Abstract] [Full Text] [PDF]

				M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk, J H Kleibeuker, M Schaapveld, and E G E de Vries Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J. Med. Genet., April 1, 2002; 39(4): 225 - 242. [Abstract] [Full Text] [PDF]

				D. Jullien, P. Vagnarelli, W. C. Earnshaw, and Y. Adachi Kinetochore localisation of the DNA damage response component 53BP1 during mitosis J. Cell Sci., January 1, 2002; 115(1): 71 - 79. [Abstract] [Full Text] [PDF]

				G. Buscemi, C. Savio, L. Zannini, F. Micciche, D. Masnada, M. Nakanishi, H. Tauchi, K. Komatsu, S. Mizutani, K. Khanna, et al. Chk2 Activation Dependence on Nbs1 after DNA Damage Mol. Cell. Biol., August 1, 2001; 21(15): 5214 - 5222. [Abstract] [Full Text] [PDF]