Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations.
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.
Shigeta
T
T
Department of Virology, The National Children's Medical Research Center, Tokyo, Japan.
Takagi
M
M
Delia
D
D
Chessa
L
L
Iwata
S
S
Kanke
Y
Y
Asada
M
M
Eguchi
M
M
Mizutani
S
S
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins; D006579:Heterozygote; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008938:Mitosis / Q000235:genetics* / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016877:Oxidants; D011506:Proteins; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases