Kool Jaap, Hamdi Mohamed, Cornelissen-Steijger Paulien, van der Eb Alex J, Terleth Carrol, van Dam Hans
Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Centre, Wassenaarseweg 72, 2333AL Leiden, The Netherlands.
Oncogene. 2003 Jul 3;22(27):4235-42. doi: 10.1038/sj.onc.1206611.
Exposure of human cells to genotoxic agents induces various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation (IR) is associated with the human diseases ataxia-telangiectasia (A-T) and Nijmegen Breakage syndrome (NBS). Here, we show that IR efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. IR was found to enhance the expression of c-Jun and, in particular, ATF3, but, in contrast to various other stress stimuli, did not induce the expression of c-Fos. Using specific inhibitors, we found that the ATM- and Nibrin1-dependent activation of ATF3 does neither require p53 nor reactive oxygen species, but is dependent on the p38 and JNK MAPkinases. Via these kinases, IR activates ATF-2, one of the transcription factors acting on the atf3 promoter. The activation of ATF-2 by IR resembles ATF-2 activation by certain growth factors, since IR mainly induced the second step of ATF-2 phosphorylation via the stress-inducible MAPkinases, phosphorylation of Thr69. As IR does not enhance ATF-2 phosphorylation in ATM and Nibrin1-deficient cells, both ATF-2 and ATF3 seem to play an important role in the protective response of human cells to IR.
将人类细胞暴露于基因毒性剂会诱导各种参与应激和DNA损伤反应执行的信号通路。对电离辐射（IR）的DNA损伤反应功能异常与人类疾病共济失调毛细血管扩张症（A-T）和尼曼匹克氏症候群（NBS）相关。在此，我们表明IR能有效诱导正常人二倍体成纤维细胞中的Jun/ATF转录因子活性，但在源自A-T和NBS患者的成纤维细胞中则不然。发现IR可增强c-Jun的表达，尤其是ATF3的表达，但与其他各种应激刺激不同的是，它不会诱导c-Fos的表达。使用特异性抑制剂，我们发现ATF3依赖ATM和Nibrin1的激活既不需要p53也不需要活性氧，但依赖于p38和JNK丝裂原活化蛋白激酶。通过这些激酶，IR激活ATF-2，ATF-2是作用于atf3启动子的转录因子之一。IR对ATF-2的激活类似于某些生长因子对ATF-2的激活，因为IR主要通过应激诱导的丝裂原活化蛋白激酶诱导ATF-2磷酸化的第二步，即苏氨酸69的磷酸化。由于IR不会增强ATM和Nibrin1缺陷细胞中ATF-2的磷酸化，因此ATF-2和ATF3似乎在人类细胞对IR的保护反应中都起着重要作用。
