Novel Function of Transcription Factor ATF5: Blockade of p53-dependent Apoptosis Induced by Ionizing Irradiation
Novel Function of Transcription Factor ATF5: Blockade of p53-dependent Apoptosis Induced by Ionizing Irradiation
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DOI：
10.1247/csf.08041
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发表时间：
2009-01-01
影响因子：
1.5
通讯作者：
Yasuda, Motoaki
中科院分区：
文献类型：
--
作者：
Nishioka, Takeshi;Miyai, Yusuke;Yasuda, Motoaki
目的：寻找影响P53依赖放射敏感性的新分子。方法与材料：采用小鼠肉瘤细胞株QRsP(P53+/+)。从该细胞系中，我们建立了一个辐射敏感克隆和一个抗辐射克隆。结果：基因芯片显示辐射敏感克隆的转录因子ATF5在体内外均显著降低。有趣的是，流式细胞仪分析显示，p53克隆腺病毒感染对辐射敏感的克隆有明显的细胞凋亡。荧光素酶报告实验显示，ATF5抑制P53和P63的反式激活活性。通过ATF5基因转移，辐射敏感克隆恢复了对电离辐射和Ad-P53感染诱导的细胞死亡的抗性。结论：ATF5可能是P53的有效抑制因子，ATF5在肿瘤中的高表达可能与肿瘤的恶性表型增强有关，如放射抵抗或细胞运动增强。
Purpose: To find a new molecule that affects p53-dependent radiosensitivity.Methods and Materials: A mouse sarcoma cell line, QRsP(p53+/+), was used. From this cell line, we established a radiosensitive clone and a radioresistant one. Colony assay, p53 gene transfer, a luciferase assay for p53 and p21, animal transplantation experiment, and DNA array analyses were performed.Results: Microarray showed marked reduction of a transcription factor, ATF5, both in vitro and in vivo for the radiosensitive clone. Interestingly, flow cytometric analysis demonstrated marked apoptosis for the radiosensitive clone by p53 cloned adenovirus infection. Luciferase reporter assay revealed that ATF5 suppressed the transactivational activity of p53 and p63. By ATF5 gene transfer, the radiosensitive clone regained resistance to both ionizing-radiation and Ad-p53 infection-induced cell death. Surprisingly, time-lapse cell migration observation revealed greater cell motility for ATF5-transfected radiosensitive clone.Conclusions: It seems likely that ATF5 is a potent repressor of p53 and elevated expression of ATF5 in a tumor may relate to enhanced malignant phenotypes, such as radioresistance or greater cell motility.