DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation.
DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation.
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种系 p53 突变细胞中 DNA 损伤相关的细胞周期失调和细胞凋亡控制。
作者：
K. Goi;Masatoshi Takagi;Satoshi Iwata;Domenico Delia;Minoru Asada;Rosangela Donghi;Yukiko Tsunematsu;Shinpei Nakazawa;Hiroshi Yamamoto;Jun Yokota;Kazuo Tamura;Y. Saeki;Joji Utsunomiya;Takashi Takahashi;R. Ueda;Chikashi Ishioka;Mariko Eguchi;Nanao Kamata;Shuki Mizutani
从5个独立的Li-Fraumeni综合征家族中建立了在残基286 A、133 R、282 W、132 E和213 ter处具有杂合p53突变的淋巴母细胞样细胞系（LCL）。当细胞周期调节响应γ-射线的研究，这些LCL显示异常G1检查点与缺陷的抑制细胞周期蛋白E/细胞周期蛋白依赖性激酶2的活性在所有情况下，除了282 W LCL，这表明正常的G1检查点。另一方面，由细胞周期蛋白A/细胞周期蛋白依赖性激酶2活性确定的S-期-G2的控制在所有这些LCL中都有缺陷。有丝分裂检查点也有缺陷的两个LCL分析为无论是有能力或无能力的G1期阻滞。当辐射诱导的细胞凋亡，这需要野生型p53功能在最佳条件下进行了研究，所有这些LCL显示出显着的失败相比，正常的LCL。这些发现表明，虽然p53依赖性的反式激活和G1-S期细胞周期控制是不稳定的失调，诱导细胞凋亡和控制细胞周期在S期-G2和有丝分裂检查点在响应DNA损伤剂是一致失调的杂合子突变LCL。这表明这些功能障碍至少部分地是Li-Fraumeni综合征家族对癌症的易感性的基础。此外，提出的方法是一个潜在的有用的方法，用于研究不同的生殖系p53突变和不同的生物学特征的个人载体。
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 gamma-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin E/cyclin-dependent kinase 2 activity in all cases 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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影响因子：
8
作者：
T. Juven;Yoav Barak;A. Zauberman;George Dl;M. Oren
通讯作者：
T. Juven;Yoav Barak;A. Zauberman;George Dl;M. Oren
影响因子：
56.9
作者：
MALKIN, D;LI, FP;FRIEND, SH
通讯作者：
FRIEND, SH
影响因子：
56.9
作者：
DULIC, V;LEES, E;REED, SI
通讯作者：
REED, SI
DOI：
10.1073/pnas.90.12.5455
发表时间：
1993-06-15
影响因子：
11.1
作者：
SZEKELY, L;SELIVANOVA, G;WIMAN, KG
通讯作者：
WIMAN, KG
突变的 p53 蛋白在体内表现出显性、负性的行为。
影响因子：
2
作者：
Hachiya,M;Chumakov,A;Miller,CW;Akashi,M;Said,J;Koeffler,HP
通讯作者：
Koeffler,HP