Kastan M B, Zhan Q, el-Deiry W S, Carrier F, Jacks T, Walsh W V, Plunkett B S, Vogelstein B, Fornace A J
Johns Hopkins Oncology Center, Baltimore, Maryland 21287.
Cell. 1992 Nov 13;71(4):587-97. doi: 10.1016/0092-8674(92)90593-2.
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.
细胞周期检查点可提高细胞存活率，并限制DNA损伤后的诱变事件。当野生型p53等位基因均被破坏时，原代小鼠成纤维细胞在由电离辐射（IR）激活的G1检查点出现缺陷。此外，患有对辐射敏感、易患癌症的疾病——共济失调毛细血管扩张症（AT）的患者的细胞，缺乏正常细胞中IR诱导的p53蛋白水平升高。最后，人类GADD45基因的IR诱导（AT细胞中该诱导也存在缺陷）依赖于野生型p53功能。野生型而非突变型p53与GADD45基因中的一个保守元件紧密结合，并且在受辐照细胞的提取物中检测到一种结合该元件的含p53核因子。因此，我们在控制DNA损伤后细胞周期停滞的信号转导途径中鉴定出三个参与者（AT基因、p53和GADD45）；该途径的异常可能促成肿瘤发展。
