title: p53 Suppresses lung resistance-related protein expression through Y-box binding protein 1 in the MCF-7 breast tumor cell line.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Tian
authors.forename: Jilai
authors.initials: J
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Song
authors.forename: Zhixian
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D005047:Etoposide; D056464:Histone Deacetylase 2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D020394:Vault Ribonucleoprotein Particles; D051840:Y-Box-Binding Protein 1; D000099187:Major Vault Protein; C495901:TP53 protein, human; C070856:YBX1 protein, human; C533423:HDAC2 protein, human