title: TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell  death.
abstract: We have identified TNFSF10 (TRAIL) as a p53-transcriptional target gene. There are two p53 DNA-binding sites in the human TNFSF10 promoter region, at 346 and 625 bp upstream of the transcription start site. A human p53-expressing adenovirus (Ad-p53) induced TRAIL mRNA and protein expression in HCT116 p53-/- human colon cancer cells. A human TRAIL-promoter reporter assay showed increased luciferase activity with the promoter vector that contains two p53 DNA-binding motifs,following Ad-p53 infection, compared to the control adenovirus infection. Using HCT116 cells, gene silencing of TNFSF10 by siRNA suppressed caspase 3 and 7 activity, even after treatment with the DNA-damaging chemotherapeutic agent adriamycin. TRAIL protein expression was elevated in adriamycin-treated breast cancer cells. In vivo, TRAIL expression was induced in mouse natural killer cells at 24 hours after systemic treatment with 5-Fluorouracil. p53-dependent TRAIL induction in natural killer cells after chemotherapy exposure provides a link between the tumor suppressor p53 and the host immune response during cancer therapy as well as a paracrine-mediated cell-extrinsic death response. Our findings provide new mechanistic insights into the signaling of p53-dependent cell death and tumor suppression, including the involvement of the host immune system and natural killer cells in vivo in the anti-tumor efficacy of chemotherapy.
authors.affiliation: Laboratory of Molecular Oncology and Cell Cycle Regulation, Institute for Translational Medicine and Therapeutics, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kageaki
authors.initials: K
authors.lastname: Kuribayashi
authors.forename: Gabriel
authors.initials: G
authors.lastname: Krigsfeld
authors.forename: Wenge
authors.initials: W
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D061945:Caspase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin