Human AP endonuclease (APE1/Ref-1) and its acetylation regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced activation of multidrug resistance gene MDR1.
Human AP endonuclease (APE1/Ref-1) and its acetylation regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced activation of multidrug resistance gene MDR1.
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DOI：
10.1038/onc.2010.435
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发表时间：
2011-01-27
期刊：
影响因子：
8
通讯作者：
Bhakat, K. K.
中科院分区：
文献类型：
--
作者：
Sengupta, S.;Mantha, A. K.;Mitra, S.;Bhakat, K. K.
人AP内切酶（APE 1/Ref-1）是DNA碱基切除修复（BER）途径中的关键酶，其过表达与肿瘤细胞对多种抗癌药物的耐药性有关。在这项研究中，我们研究了APE 1的转录调节（非修复）功能的分子基础，促进对某些类型的药物的耐药性。我们最近发现APE 1与Y-box-binding protein 1（YB-1）稳定地相互作用，并作为其共激活因子参与多药耐药基因MDR 1的表达，从而导致耐药。在这里，我们首次表明，APE 1是稳定相关的基本转录因子RNA聚合酶II（RNA聚合酶II）和内源性MDR 1启动子上的共激活因子p300。APE 1的缺失显著减少了YB-1/p300向启动子的募集，导致RNA pol II负载减少。p300介导的药物诱导的APE 1乙酰化增强了MDR 1启动子上乙酰化APE 1（AcAPE 1）/YB-1/p300复合物的形成。该复合物的增强募集增加了MDR 1启动子依赖性荧光素酶活性及其内源性表达。使用APE 1下调的细胞和过表达野生型APE 1或其非乙酰化突变体的细胞，我们已经证明APE 1的乙酰化的损失损害了MDR 1的活化，并使细胞对顺铂或依托泊苷敏感。因此，我们已经建立了APE 1的乙酰化依赖性调节功能诱导MDR 1介导的耐药的基础。
Overexpression of human AP-endonuclease (APE1/Ref-1), a key enzyme in the DNA base excision repair (BER) pathway, is often associated with tumor cell resistance to various anticancer drugs. In this study, we examined the molecular basis of transcriptional regulatory (non repair) function of APE1 in promoting resistance to certain types of drugs. We have recently shown that APE1 stably interacts with Y-box-binding protein 1 (YB-1), and acts as its coactivator for the expression of multidrug resistance gene MDR1, thereby causing drug-resistance. Here we show for the first time that APE1 is stably associated with the basic transcription factor RNA polymerase II (RNA pol II) and the coactivator p300 on the endogenous MDR1 promoter. APE1’s depletion significantly reduces YB-1/p300 recruitment to the promoter, resulting in reduced RNA pol II loading. Drug-induced APE1 acetylation which is mediated by p300 enhances formation of acetylated APE1 (AcAPE1)/YB-1/p300 complex on the MDR1 promoter. Enhanced recruitment of this complex increases MDR1 promoter dependent luciferase activity and its endogenous expression. Using APE1 downregulated cells and cells overexpressing wild type APE1 or its nonacetylable mutant we have demonstrated that the loss of APE1’s acetylation impaired MDR1 activation and sensitizes the cells to cisplatin or etoposide. We have thus established the basis for APE1’s acetylation-dependent regulatory function in inducing MDR1-mediated drug resistance.
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影响因子：
6.6
作者：
Bapat A;Fishel ML;Kelley MR
通讯作者：
Kelley MR
影响因子：
11.5
作者：
Bobola, MS;Finn, LS;Silber, JR
通讯作者：
Silber, JR
影响因子：
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作者：
Das, Soumita;Chattopadhyay, Ranajoy;Hazra, Tapas K.
通讯作者：
Hazra, Tapas K.
影响因子：
5.3
作者：
Cho, H;Orphanides, G;Reinberg, D
通讯作者：
Reinberg, D
DOI：
10.1093/jnci/85.8.632
发表时间：
1993-04-21
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
CHAUDHARY, PM;RONINSON, IB
通讯作者：
RONINSON, IB