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 journalArticle

39 Citations (Scopus)

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

Fingerprint

M Phase Cell Cycle Checkpoints
Ataxia Telangiectasia
Apoptosis
Mutation
Ataxia Telangiectasia Mutated Proteins
Radiation Tolerance
Haploinsufficiency
Neoplasms
Mutant Proteins
Epidemiologic Studies
X-Rays
Cell Line
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Shigeta, T., Takagi, M., Delia, D., Chessa, L., Iwata, S., Kanke, Y., ... Mizutani, S. (1999). Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Research, 59(11), 2602-2607.

Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. / Shigeta, Teruko; Takagi, Masatoshi; Delia, Domenico; Chessa, Luciana; Iwata, Satoshi; Kanke, Yusuke; Asada, Minoru; Eguchi, Mariko; Mizutani, Shuki.

In: Cancer Research, Vol. 59, No. 11, 01.06.1999, p. 2602-2607.

Research output: Contribution to journalArticle

Shigeta, T, Takagi, M, Delia, D, Chessa, L, Iwata, S, Kanke, Y, Asada, M, Eguchi, M & Mizutani, S 1999, 'Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations', Cancer Research, vol. 59, no. 11, pp. 2602-2607.
Shigeta T, Takagi M, Delia D, Chessa L, Iwata S, Kanke Y et al. Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Research. 1999 Jun 1;59(11):2602-2607.
Shigeta, Teruko ; Takagi, Masatoshi ; Delia, Domenico ; Chessa, Luciana ; Iwata, Satoshi ; Kanke, Yusuke ; Asada, Minoru ; Eguchi, Mariko ; Mizutani, Shuki. / Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. In: Cancer Research. 1999 ; Vol. 59, No. 11. pp. 2602-2607.
@article{73a2daa6f4e74152884f02f83f0352b8,
title = "Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations",
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.",
author = "Teruko Shigeta and Masatoshi Takagi and Domenico Delia and Luciana Chessa and Satoshi Iwata and Yusuke Kanke and Minoru Asada and Mariko Eguchi and Shuki Mizutani",
year = "1999",
month = "6",
day = "1",
language = "English",
volume = "59",
pages = "2602--2607",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations

AU - Shigeta, Teruko

AU - Takagi, Masatoshi

AU - Delia, Domenico

AU - Chessa, Luciana

AU - Iwata, Satoshi

AU - Kanke, Yusuke

AU - Asada, Minoru

AU - Eguchi, Mariko

AU - Mizutani, Shuki

PY - 1999/6/1

Y1 - 1999/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033153140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033153140&partnerID=8YFLogxK

M3 - Article

VL - 59

SP - 2602

EP - 2607

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 11

ER -