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| Defective control of apoptosis, radiosensitivity, and spindle checkpoint in ataxia telangiectasia |
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| Author(s): Takagi M, Delia D, Chessa L, Iwata S, Shigeta T, Kanke Y, Goi K, Asada M, Eguchi M, Kodama C, Mizutani S |
| Source: CANCER RESEARCH Volume: 58 Issue: 21 Pages: 4923-4929 Published: NOV 1 1998 |
| Times Cited: 38 References: 52 |
| Abstract: We examined the regulation of apoptosis, radiosensitivity, and spindle checkpoint in response to DNA-damaging agents in ataxia telangiectasia (AT)-derived lymphoblastoid cell lines (AT-LCLs), which lack AT mutated (ATM) protein expression. In addition to the previous findings that AT-LCLs are defective in regulation of cell cycle at the G(1), S, and G(2)-M checkpoints in response to X-ray irradiation (X-IR) and are highly sensitive to X-IR (J. Biol. Chem., 271: 20486-20493, 1996), we showed for the first time that AT-LCLs were defective in X-IR-associated spindle checkpoint control. The cells were also resistant to early apoptosis as much as LCLs derived from patients with Li-Fraumeni syndrome (LFS-LCLs). Terminal deoxynucleotidyl transferase-mediated nick end labeling assay of LCLs, however, demonstrated a significant increase in apoptotic cells among AT-LCLs cultured over a longer period after X-IR. These findings were in contrast to those of LFS-LCL, which showed very little increase in terminal deoxynucleotidyl transferase-mediated nick end labeling-positive population, even in cells with hyperploidy. Thus, although early apoptosis and cell cycle controls in response to DNA damage are disrupted in broth ATM and p53 mutations, cells from AT patients are much more susceptible to late-onset apoptosis than those of LFS. These differences may depend on the level of accumulation of DNA damage and/or threshold that triggers late-onset cell death in ATM or p53 mutations. Our findings allow a better understanding of the role of ATM in p53-dependent and independent signal transduction pathways in response to DNA damaging agents. |
| Document Type: Article |
| Language: English |
| Reprint Address: Mizutani, S (reprint author), Natl Childrens Med Res Ctr, Dept Virol, Setagaya Ku, 3-35-31 Taishido, Tokyo 154, Japan |
Addresses:
1. Natl Childrens Med Res Ctr, Dept Virol, Setagaya Ku, Tokyo 154, Japan
2. Inst Nazl Tumori, Div Oncol Sperimentale, I-20133 Milan, Italy
3. Univ La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy
4. Univ Tokyo, Dept Nutr, Tokyo 113, Japan
5. Hiroshima Univ, Dept Canc Cytogenet, Res Inst Radiat Biol & Med, Hiroshima 734, Japan
6. Veritas Co Ltd, Tokyo 105, Japan |
| Publisher: AMER ASSOC CANCER RESEARCH, PO BOX 11806, BIRMINGHAM, AL 35202 USA |
| Subject Category: Oncology |
| IDS Number: 134XE |
| ISSN: 0008-5472 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |