p53 suppresses lung resistance‐related protein expression through Y‐box binding protein 1 in the MCF‐7 breast tumor cell line
p53 suppresses lung resistance‐related protein expression through Y‐box binding protein 1 in the MCF‐7 breast tumor cell line
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DOI：
10.1002/jcp.22700
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发表时间：
2011-12
影响因子：
5.6
通讯作者：
Bao-lei Tian;Ji-Long Liu;Bin Liu;Yan Dong;Jinfeng Liu;Yi Song;Zhi-xian Sun
中科院分区：
文献类型：
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作者：
Bao-lei Tian;Ji-Long Liu;Bin Liu;Yan Dong;Jinfeng Liu;Yi Song;Zhi-xian Sun
肺耐药相关蛋白（LRP）在肿瘤细胞的多药耐药中发挥作用。了解LRP在肿瘤细胞中表达的调控机制是一个重要的研究领域。在LRP启动子中发现了一个p53反应元件，因此本研究探讨了p53相关的LRP表达调控。我们首先证明，p53过表达抑制LRP表达在蛋白质和mRNA水平。然后，使用双荧光素酶报告基因测定，我们将p53反应元件定位于LRP启动子的Y-box（-263-407），即YB-1结合位点，但不是推定的p53反应元件。此外，免疫共沉淀和染色质免疫沉淀显示，p53可以通过与YB-1的相互作用与LRP启动子的Y-box结合。YB-1与p53的共表达促进了p53诱导的MCF-7细胞内源性LRP表达的抑制。HDAC 2是p53的辅阻遏物，也被发现与YB-1相互作用，这种相互作用是由p53介导的。这些结果表明，p53-HDAC 2转录抑制因子复合物可以结合LRP启动子的Y-盒，并通过与YB-1相互作用抑制LRP表达。p53相关的LRP表达抑制被阿霉素治疗和Adr完全逆转，而CP和VP-16治疗诱导LRP表达显著增加。通过siRNA抑制LRP表达促进Adr诱导的MCF-7细胞凋亡。所有这些结果表明，LRP的p53相关抑制的丧失可能是LRP表达增加的原因，因此，肿瘤细胞的化疗耐药性。J.细胞。226：3433-3441，2011。© 2011 Wiley Periodicals，Inc.
Lung resistance‐related protein (LRP) has roles in multi‐drug resistance of tumor cells. Understanding the mechanisms that regulate LRP expression in tumor cells is an important research area. A putative p53 response element in the LRP promoter has been found. Thus, p53‐related regulation of LRP expression was explored in this study. We first demonstrated that p53 overexpression inhibited LRP expression both at the protein and mRNA levels. Then, using a dual‐luciferase reporter assay, we located the p53 response element to the Y‐box (−263∼−407) of the LRP promoter, the YB‐1 binding site, but not the putative p53 response element. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation showed p53 could bind to the Y‐box of the LRP promoter through interaction of p53 with YB‐1. YB‐1 coexpression with p53 facilitated p53‐induced suppression of endogenous LRP expression in MCF‐7 cells. HDAC2, a corepressor of p53, was found to also interact with YB‐1, and this interaction was mediated by p53. These results showed that the p53‐HDAC2 transcriptional repressor complex can bind to the Y‐box of the LRP promoter and repress LRP expression through interaction with YB‐1. p53‐related suppression of LRP expression was completely reversed by doxorubicin treatment and Adr, whereas CP and VP‐16 treatment induced LRP expression increased significantly. Inhibition of LRP expression by siRNA facilitated Adr induced apoptosis of MCF‐7 cells. All these findings indicated that loss of p53‐related suppression of LRP may be the reason for LRP expression increase, and, therefore, chemotherapy resistance in tumor cells. J. Cell. Physiol. 226: 3433–3441, 2011. © 2011 Wiley Periodicals, Inc.