Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage.
Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage.
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DOI：
10.1093/nar/gkm1173
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发表时间：
2008-03
影响因子：
14.9
通讯作者：
Bhakat KK
中科院分区：
文献类型：
--
作者：
Zaky A;Busso C;Izumi T;Chattopadhyay R;Bassiouny A;Mitra S;Bhakat KK
人AP-内切核酸酶（APE 1/Ref-1）是一种重要的多功能蛋白质，通过DNA碱基切除修复（BER）途径在氧化性碱基损伤的修复中发挥重要作用。哺乳动物AP-内切核酸酶（APE 1）过表达经常在肿瘤细胞中观察到，并且赋予对各种抗癌药物的抗性;其下调通过诱导细胞凋亡使肿瘤细胞对那些药剂敏感。在这里，我们表明，野生型（WT），而不是突变型p53负调控APE 1的表达。在人大肠癌细胞系HCT 116 p53（+/+）中观察到APE 1 mRNA和蛋白水平的时间依赖性降低，但在等基因p53无效突变体中未观察到。此外，异位表达的WTP 53在p53空细胞显着降低内源性APE 1和APE 1启动子依赖性荧光素酶的表达在剂量依赖性的方式。染色质免疫沉淀分析显示，内源性p53结合到APE 1启动子区，包括一个Sp1位点。我们在这里表明，WTP 53干扰Sp1结合的APE 1启动子，这提供了一个机制，APE 1的下调。综上所述，我们的研究结果表明，WTP 53是APE 1表达的负调节因子，因此，抑制APE 1的p53可以提供一个额外的途径，p53依赖性诱导细胞凋亡的DNA损伤。
The human AP-endonuclease (APE1/Ref-1), an essential multifunctional protein, plays a central role in the repair of oxidative base damage via the DNA base excision repair (BER) pathway. The mammalian AP-endonuclease (APE1) overexpression is often observed in tumor cells, and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to those agents via induction of apoptosis. Here we show that wild type (WT) but not mutant p53 negatively regulates APE1 expression. Time-dependent decrease was observed in APE1 mRNA and protein levels in the human colorectal cancer line HCT116 p53(+/+), but not in the isogenic p53 null mutant after treatment with camptothecin, a DNA topoisomerase I inhibitor. Furthermore, ectopic expression of WTp53 in the p53 null cells significantly reduced both endogenous APE1 and APE1 promoter-dependent luciferase expression in a dose-dependent fashion. Chromatin immunoprecipitation assays revealed that endogenous p53 is bound to the APE1 promoter region that includes a Sp1 site. We show here that WTp53 interferes with Sp1 binding to the APE1 promoter, which provides a mechanism for the downregulation of APE1. Taken together, our results demonstrate that WTp53 is a negative regulator of APE1 expression, so that repression of APE1 by p53 could provide an additional pathway for p53-dependent induction of apoptosis in response to DNA damage.
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影响因子：
10.5
作者：
Jayaraman, L;Murthy, KGK;Prives, C
通讯作者：
Prives, C
DOI：
10.1016/s0360-3016(00)01561-3
发表时间：
2001-05-01
影响因子：
7
作者：
Koukourakis, MI;Giatromanolaki, A;Harris, AL
通讯作者：
Harris, AL
影响因子：
16
作者：
Hermeking, H;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
DNA修复酶的水平人类肾上腺素/阿哌丁丁核酸内切酶（APE1，APEX，REF-1）与宫颈癌的内在放射敏性有关。
影响因子：
8.8
作者：
Herring, CJ;West, CML;Wilks, DP;Davidson, SE;Hunter, RD;Berry, P;Forster, G;MacKinnon, J;Rafferty, JA;Elder, RH;Hendry, JH;Margison, GP
通讯作者：
Margison, GP
影响因子：
8
作者：
Grombacher, T;Eichhorn, U;Kaina, B
通讯作者：
Kaina, B