Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway
Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway
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DOI：
10.1038/sj.onc.1205981
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发表时间：
2002-11-07
期刊：
影响因子：
8
通讯作者：
Ball, KL
中科院分区：
文献类型：
--
作者：
Pamment, J;Ramsay, E;Ball, KL
基因毒性应激诱导IRF-1的机制以及在DNA损伤反应中这种抑癌转录因子上游的信号成分尚不清楚。我们证明了IRF-1和肿瘤抑制蛋白P53在对DNA损伤的反应中以ATM依赖的方式协同上调。电离辐射(IR)或依托泊苷通过增加IRF-1的表达/合成和延长IRF-1蛋白的半衰期来诱导IRF-1蛋白的表达。在ATM缺陷细胞中观察到IRF-1mRNA和IRF-1蛋白的诱导存在显著缺陷。虽然ATM缺陷细胞未能在基因毒性应激中增加IRF-1，但对病毒模拟的IRF-1的诱导仍然完好无损。ATM激酶在AT细胞中的重新表达恢复了IRF-1的DNA损伤诱导能力，而PI-3激酶抑制剂Wortmannin则抑制了ATM阳性细胞中DNA损伤诱导的IRF-1。这些数据强调了ATM激酶在协调IRF-1和P53的协同诱导和转录合作以调节p21表达中的作用。因此，IRF-1由两条不同的信号通路控制：病毒感染细胞中的JAK/STAT信号通路和DNA损伤细胞中的ATM信号通路。
The mechanism by which genotoxic stress induces IRF-1 and the signalling components upstream of this anti-oncogenic transcription factor during the response to DNA damage are not known. We demonstrate that IRF-1 and the tumour suppressor protein p53 are coordinately up-regulated during the response to DNA damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing radiation (IR) or etoposide occurs through a concerted mechanism involving increased IRF-1 expression/synthesis and an increase in the half-life of the IRF-1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1 protein was observed in ATM deficient cells. Although ATM deficient cells failed to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in response to viral mimetics remained intact. Re-expression of the ATM kinase in AT cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive cells. The data highlight a role for the ATM kinase in orchestrating the coordinated induction and transcriptional cooperation of IRF-1 and p53 to regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM-signalling pathway in DNA damaged cells.