Tanaka N, Ishihara M, Lamphier M S, Nozawa H, Matsuyama T, Mak T W, Aizawa S, Tokino T, Oren M, Taniguchi T
Department of Immunology, Faculty of Medicine, University of Tokyo, Japan.
Nature. 1996 Aug 29;382(6594):816-8. doi: 10.1038/382816a0.
Normally growing cells promptly cease DNA synthesis when exposed to genotoxic stresses, such as radiation, and this cell-cycle arrest prevents the accumulation of mutations. The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system, inhibits cell growth, and manifests tumour-suppressor activities. Here we show that mouse embryonic fibroblasts (EFs) lacking IRF-1 are deficient in their ability to undergo DNA-damage-induced cell-cycle arrest. A similar phenotype has been observed in EFs lacking the tumour suppressor p53 (refs 8, 9), although the expression of IRF-1 and p53 are independent of one another. Furthermore, we show that transcriptional induction of the gene encoding p21 (WAF1, CIP1), a cell-cycle inhibitor, by gamma-irradiation is dependent on both p53 and IRF-1, and that the p21 promoter is activated, either directly or indirectly, by both in a transient cotransfection assay. These two tumour-suppressor transcription factors therefore converge functionally to regulate the cell cycle through the activation of a common target gene.
正常生长的细胞在受到辐射等基因毒性应激时会迅速停止DNA合成，这种细胞周期停滞可防止突变的积累。转录因子干扰素调节因子（IRF）-1对于干扰素系统的调节至关重要，它抑制细胞生长并表现出肿瘤抑制活性。我们在此表明，缺乏IRF-1的小鼠胚胎成纤维细胞（EFs）在经历DNA损伤诱导的细胞周期停滞方面能力不足。在缺乏肿瘤抑制因子p53的EFs中也观察到了类似的表型（参考文献8、9），尽管IRF-1和p53的表达彼此独立。此外，我们表明，γ射线照射对编码细胞周期抑制剂p21（WAF1、CIP1）的基因的转录诱导依赖于p53和IRF-1两者，并且在瞬时共转染实验中，p21启动子会被两者直接或间接激活。因此，这两种肿瘤抑制转录因子在功能上汇聚，通过激活一个共同的靶基因来调节细胞周期。
