title: Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity.
abstract: Decoy receptor 2 (DcR2) is one of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and suppresses TRAIL-induced apoptosis. Its expression, like the other three TRAIL receptors (i.e., DR4, DR5, and DcR1), is regulated by p53. Here, we report that DcR2 is a p53 target gene and regulates chemosensitivity. In this study, we identified a p53-binding site (p53BS) in the first intron of the DcR2 gene. This p53BS is almost identical to the ones found in the first introns of other three TRAIL receptor genes. By a chromatin immunoprecipitation assay, we detected that the p53 protein bound to the DcR2 p53BS in intact cells. Subcloning of the DcR2 p53BS into a luciferase reporter vector driven by a SV40 promoter exhibited enhanced luciferase activity when transiently cotransfected with a wild-type (wt) p53 expression vector in p53-null cell lines or stimulated with DNA-damaging agents in cell lines having wt p53. Moreover, when the DcR2 p53BS, together with its own corresponding promoter regions, was subcloned into a basic luciferase vector without a promoter element, its transcriptional activities were strikingly increased by cotransfection of the wt p53 gene. However, when this p53BS was deleted from the construct, wt p53 failed to transactivate this reporter construct. Collectively, we conclude that p53 directly regulates the DcR2 gene expression via an intronic p53BS. In addition, overexpression of DcR2 conferred resistance to TRAIL-mediated apoptosis and attenuated cell response to DNA-damaging agents, whereas silencing of DcR2 expression enhanced chemotherapeutic agent-induced apoptosis. These results suggest that DcR2 regulates chemosensitivity.
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D007438:Introns; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D015533:Transcriptional Activation; D014162:Transfection; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin