DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent promoter activity via Sp1 phosphorylation
DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent promoter activity via Sp1 phosphorylation
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DOI：
10.1111/j.1349-7006.2007.00476.x
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发表时间：
2007-06-01
期刊：
影响因子：
5.7
通讯作者：
Kohno, Kimitoshi
中科院分区：
文献类型：
--
作者：
Niina, Ichiro;Uchiumi, Takeshi;Kohno, Kimitoshi
抗癌药物对转录因子的修饰在细胞凋亡和存活信号传导中起着重要作用。在这里，我们报告，DNA拓扑异构酶I和II抑制剂，如SN-38和依托泊苷，但不是顺铂，5-氟尿嘧啶或放线菌素D，可以诱导转录因子Sp1的磷酸化。此外，DNA拓扑异构酶抑制剂显示反式激活GC盒依赖性启动子，如SV 40和血管内皮生长因子启动子。在足叶乙甙处理的30分钟内可检测到磷酸化形式的Sp1，并且通过PI 3 K抑制剂渥曼青霉素的存在和DNA依赖性蛋白激酶（DNA-PK）敲低而大大减少。我们还证实了磷酸化形式的DNA-PK通过用依托泊苷和SN-38处理而增加。综上所述，这些发现证明了一种新的基因组对诱导Sp1磷酸化的抗癌药物的反应，并可能有助于肿瘤进展和耐药性。
Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA topoisomerase I and II inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA topoisomerase inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.