title: ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3.
abstract: Activating transcription factor (ATF) 3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. Although the ATF3 homodimer is known to repress transcription of several genes, its precise biological roles are still unclear. In this study, we investigated the functional role of ATF3 in doxorubicin (DOX=adriamycin)-treated neonatal rat cardiac myocytes. DOX rapidly activated JNK and c-Jun and induced ATF3 at both mRNA and protein level. Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay. It was further shown that p53, one of the apoptosis-inducing transcription factors, was downregulated in the ATF3-overexpressing cardiomyocytes. These results strongly suggest that ATF3 may function as a cytoprotective transcription factor in DOX-treated cardiac myocytes, at least in part, owing to downregulation of p53. ATF3 may be a novel therapeutic target that protects cardiac myocytes from DOX-induced apoptosis.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nobori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Mimi
authors.initials: M
authors.lastname: Tamamori-Adachi
authors.forename: Susumu
authors.initials: S
authors.lastname: Adachi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ono
authors.forename: Junya
authors.initials: J
authors.lastname: Kawauchi
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Kitajima
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Marumo
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D051700:Activating Transcription Factor 3; D051696:Activating Transcription Factors; D017209:Apoptosis / Q000187:drug effects*; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; D051696:Activating Transcription Factors; D001798:Blood Proteins; D046911:Macromolecular Substances; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases