Torigoe Takayuki, Izumi Hiroto, Wakasugi Tetsuro, Niina Ichiro, Igarashi Tomonori, Yoshida Takeshi, Shibuya Izumi, Chijiiwa Kazuo, Matsuo Ken-ichi, Itoh Hideaki, Kohno Kimitoshi
Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Fukuka, Japan.
J Biol Chem. 2005 Jan 14;280(2):1179-85. doi: 10.1074/jbc.M410499200. Epub 2004 Nov 8.
Drug-induced modifications of transcription factors play important roles in both apoptosis and survival signaling. The data presented here show that the DNA topoisomerase II poison TAS-103 transactivated the SV40 promoter in a GC-box-dependent manner and induced Sp1 acetylation in cells expressing p300. This activity was not observed in cells lacking p300. TAS-103 treatment also enhanced the p300 content of the nucleus and the interaction of p300 with Sp1. Cellular susceptibility to TAS-103 was correlated with p300 expression but not with topoisomerase II expression. Furthermore, the presence of p300 significantly sensitized cancer cells to TAS-103 but not to cisplatin. Taken together, these findings demonstrate novel genomic responses to anticancer agents that modulate Sp1 acetylation and Sp1-dependent transcription in an apoptotic pathway.
药物诱导的转录因子修饰在细胞凋亡和生存信号传导中均发挥重要作用。本文提供的数据表明，DNA拓扑异构酶II毒药TAS-103以GC盒依赖的方式反式激活SV40启动子，并在表达p300的细胞中诱导Sp1乙酰化。在缺乏p300的细胞中未观察到这种活性。TAS-103处理还增加了细胞核中p300的含量以及p300与Sp1的相互作用。细胞对TAS-103的敏感性与p300表达相关，而与拓扑异构酶II表达无关。此外，p300的存在显著使癌细胞对TAS-103敏感，但对顺铂不敏感。综上所述，这些发现证明了抗癌药物在凋亡途径中调节Sp1乙酰化和Sp1依赖性转录的新基因组反应。
