Dual regulatory roles of human AP-endonuclease (APE1/Ref-1) in CDKN1A/p21 expression.
Dual regulatory roles of human AP-endonuclease (APE1/Ref-1) in CDKN1A/p21 expression.
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人AP-核酸酶（APE1/REF-1）在CDKN1A/P21表达中的双重调节作用。
DOI：
10.1371/journal.pone.0068467
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bhakat KK
中科院分区：
文献类型：
--
作者：
Sengupta S;Mitra S;Bhakat KK
人AP-核酸内切酶（APE 1/Ref-1）是一种参与DNA氧化损伤修复和转录调控的重要多功能蛋白质，通常在肿瘤细胞中过表达。APE 1可刺激p53的DNA结合，并在细胞周期蛋白依赖性激酶抑制剂p21（CDKN 1A）基因的表达中起反式激活作用。在这里，我们展示了APE 1与p53顺式元件的稳定结合，所述顺式元件是表达p53的野生型HCT 116细胞中p53介导的p21活化所需的。然而，令人惊讶的是，我们观察到APE 1依赖的抑制p21在同基因p53-null HCT 116细胞。p53在p53-null细胞中的异位表达废除了这种抑制，表明APE 1在p21表达中的负调节作用依赖于p53状态。然后，我们在p21近端启动子区鉴定了APE 1的另一个结合位点，该位点包含AP 4（p21的抑制子）的顺式元件。有趣的是，APE 1和AP 4对p21的抑制表现出相互依赖性。此外，p53-null细胞中的异位p53抑制了AP 4与APE 1的结合，它们与启动子的结合和p21的抑制。这些结果共同确立了APE 1作为p21基因的共激活子或共抑制子的作用，依赖于p53状态。因此，很可能APE 1过表达和p53失活，通常在肿瘤细胞中观察到，通过组成性下调p21表达促进肿瘤细胞增殖。
The human AP-endonuclease (APE1/Ref-1), an essential multifunctional protein involved in repair of oxidative DNA damage as well as in transcriptional regulation, is often overexpressed in tumor cells. APE1 was earlier shown to stimulate p53’s DNA binding and its transactivation function in the expression of cyclin-dependent kinase inhibitor p21 (CDKN1A) gene. Here, we show APE1’s stable binding to p53 cis elements which are required for p53-mediated activation of p21 in p53-expressing wild type HCT116 cells. However, surprisingly, we observed APE1-dependent repression of p21 in isogenic p53-null HCT116 cells. Ectopic expression of p53 in the p53-null cells abrogated this repression suggesting that APE1’s negative regulatory role in p21 expression is dependent on the p53 status. We then identified APE1’s another binding site in p21’s proximal promoter region containing cis elements for AP4, a repressor of p21. Interestingly, APE1 and AP4 showed mutual dependence for p21 repression. Moreover, ectopic p53 in p53-null cells inhibited AP4’s association with APE1, their binding to the promoter and p21 repression. These results together establish APE1’s role as a co-activator or co-repressor of p21 gene, dependent on p53 status. It is thus likely that APE1 overexpression and inactivation of p53, often observed in tumor cells, promote tumor cell proliferation by constitutively downregulating p21 expression.
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