TY - JOUR
T1 - DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation
AU - Goi, Kumiko
AU - Takagi, Masatoshi
AU - Iwata, Satoshi
AU - Delia, Domenico
AU - Asada, Minoru
AU - Donghi, Rosangela
AU - Tsunematsu, Yukiko
AU - Nakazawa, Shinpei
AU - Yamamoto, Hiroshi
AU - Yokota, Jun
AU - Tamura, Kazuo
AU - Saeki, Yoshifumi
AU - Utsunomiya, Joji
AU - Takahashi, Takashi
AU - Ueda, Ryuzo
AU - Ishioka, Chikashi
AU - Eguchi, Mariko
AU - Kamata, Nanao
AU - Mizutani, Shuki
PY - 1997/5/15
Y1 - 1997/5/15
N2 - Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from five independent Li-Fraumeni syndrome families. When cell cycle regulation in response to γ-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin F/cyclindependent kinase 2 activity in all eases except for 282W LCL which showed a normal G1 checkpoint. On the other hand, the control of S-phase-G2 as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G1 arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G1-S- phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G2 and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.
AB - Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from five independent Li-Fraumeni syndrome families. When cell cycle regulation in response to γ-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin F/cyclindependent kinase 2 activity in all eases except for 282W LCL which showed a normal G1 checkpoint. On the other hand, the control of S-phase-G2 as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G1 arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G1-S- phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G2 and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.
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M3 - Article
C2 - 9157982
AN - SCOPUS:15444355378
VL - 57
SP - 1895
EP - 1902
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 10
ER -