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p53 suppresses lung resistance‐related protein expression through Y‐box binding protein 1 in the MCF‐7 breast tumor cell line
Author(s) -
Tian Baolei,
Liu Jilai,
Liu Bin,
Dong Yan,
Liu Jinfeng,
Song Yi,
Sun Zhixian
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22700
Subject(s) - chromatin immunoprecipitation , corepressor , repressor , microbiology and biotechnology , biology , immunoprecipitation , cancer research , promoter , gene silencing , gene expression , cell culture , chemistry , gene , biochemistry , genetics
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.