title: Key role of ATF3 in p53-dependent DR5 induction upon DNA damage of human colon cancer cells.
abstract: Stress response gene ATF3 is one of the p53 target genes and has a tumor suppressor role in cancer. However, the biological role of p53-ATF3 pathway is not well understood. Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), and a combination of TRAIL and agents that increase the expression of DR5 is expected as a novel anticancer therapy. In this report, we demonstrate that ATF3 is required for efficient DR5 induction upon DNA damage by camptothecin (CPT) in colorectal cancer cells. In the absence of ATF3, induction of DR5 messenger RNA and protein is remarkably abrogated, and this is associated with reduced cell death by TRAIL and CPT. By contrast, exogenous expression of ATF3 causes more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/CPT. Reporter assay and DNA affinity precipitation assay demonstrate that at least three ATF/CRE motifs at the proximal promoter of the human DR5 gene are involved in the activation of DNA damage-induced DR5 gene transcription. Furthermore, ATF3 is shown to interact with p53 to form a complex on the DR5 gene by Re-chromatin immunoprecipitation assay. Taken together, our results provide a novel insight into the role of ATF3 as an essential co-transcription factor for p53 upon DNA damage, and this may represent a useful biomarker for TRAIL-based anticancer therapy.
authors.affiliation: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Taketani
authors.forename: J
authors.initials: J
authors.lastname: Kawauchi
authors.forename: M
authors.initials: M
authors.lastname: Tanaka-Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Ishizaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: J
authors.initials: J
authors.lastname: Miyoshi
authors.forename: Y
authors.initials: Y
authors.lastname: Maehara
authors.forename: S
authors.initials: S
authors.lastname: Kitajima
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D002166:Camptothecin