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 language | English |
|---|---|
| Pages (from-to) | 2602-2607 |
| Number of pages | 6 |
| Journal | Cancer Research |
| Volume | 59 |
| Issue number | 11 |
| Publication status | Published - Jun 1 1999 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0033153140&partnerID=8YFLogxK
M3 - Article
C2 - 10363981
AN - SCOPUS:0033153140
VL - 59
SP - 2602
EP - 2607
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 11
ER -