Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations

Teruko Shigeta, Masatoshi Takagi, Domenico Delia, Luciana Chessa, Satoshi Iwata, Yusuke Kanke, Minoru Asada, Mariko Eguchi, Shuki Mizutani

Research output: Contribution to journalArticlepeer-review

Abstract

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 carders 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.

Original languageEnglish
Pages (from-to)2602-2607
Number of pages6
JournalCancer Research
Volume59
Issue number11
Publication statusPublished - Jun 1 1999

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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