A MAMMALIAN-CELL CYCLE CHECKPOINT PATHWAY UTILIZING P53 AND GADD45 IS DEFECTIVE IN ATAXIA-TELANGIECTASIA
A MAMMALIAN-CELL CYCLE CHECKPOINT PATHWAY UTILIZING P53 AND GADD45 IS DEFECTIVE IN ATAXIA-TELANGIECTASIA
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DOI：
10.1016/0092-8674(92)90593-2
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发表时间：
1992-11-13
期刊：
影响因子：
64.5
通讯作者：
FORNACE, AJ
中科院分区：
文献类型：
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作者：
KASTAN, MB;ZHAN, QM;FORNACE, AJ
细胞周期检查点可以提高细胞存活率并限制DNA损伤后的诱变事件。原代鼠成纤维细胞成为缺乏G1检查点激活电离辐射（IR）时，两个野生型p53等位基因被破坏。 此外，来自具有放射敏感性、癌症易感性疾病共济失调-毛细血管扩张症（AT）患者的细胞缺乏在正常细胞中观察到的IR诱导的p53蛋白水平增加。最后，IR诱导的人GADD 45基因，一种诱导，也是有缺陷的AT细胞，依赖于野生型p53的功能。野生型，但不是突变型p53强烈绑定到GADD 45基因中的保守元件，和一个含有p53的核因子，结合这个元素，从辐照细胞提取物中检测到。因此，我们确定了三个参与者（AT基因，p53和GADD 45）的信号转导通路，控制细胞周期停滞后DNA损伤;这一途径的异常可能有助于肿瘤的发展。
Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In addition, cells from patients with the radiosensitive, cancer-prone disease ataxia-telangiectasia (AT) lacked the IR-induced increase in p53 protein levels seen in normal cells. Finally, IR induction of the human GADD45 gene, an induction that is also defective in AT cells, was dependent on wild-type p53 function. Wild-type but not mutant p53 bound strongly to a conserved element in the GADD45 gene, and a p53-containing nuclear factor, which bound this element, was detected in extracts from irradiated cells. Thus, we identified three participants (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.