title: Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation.
abstract: Activating transcription factor 3 (ATF3) is induced and functions both as a cellular response to stress and to stimulate proliferation in multiple tissues. However, in the nervous system ATF3 is expressed only in injured neurons. Here we reveal a function of ATF3 in neurons under death stress. Overexpression of ATF3 by adenovirus inhibits the mitogen-activated kinase kinase kinase 1 (MEKK1)-c-Jun N-Terminal Kinase (JNK)-induced apoptosis and induces neurite elongation via Akt activation in PC12 cells and superior nerve ganglion neurons. A DNA microarray study reveals that ATF3 expression and JNK activation induce expression of the heat shock protein 27 (Hsp27). Immunoprecipitation analysis and promoter assay for Hsp27 expression suggest that both ATF3 and c-Jun are necessary for transcriptional activation of Hsp27. Hsp27 expression significantly inhibits JNK-induced apoptosis as well as Akt activation in PC12 cells and superior cervical ganglion neurons. We conclude that the combination of ATF3 and c-Jun induces the anti-apoptotic factor Hsp27, which directly or indirectly activates Akt, and thereby possibly inhibits apoptosis and induces nerve elongation. Our results suggest that ATF3- and c-Jun-induced Hsp27 expression is a novel survival response in neurons under death stress such as nerve injury.
authors.affiliation: Department of Anatomy and Neurobiology, Osaka City University, Graduate School of Medicine, Osaka 545-8585, Japan.
authors.forename: Saya
authors.initials: S
authors.lastname: Nakagomi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Namikawa
authors.forename: Sumiko
authors.initials: S
authors.lastname: Kiryu-Seo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyama
mesh_terms: D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007002:Hypoglossal Nerve / Q000166:cytology / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017783:Superior Cervical Ganglion / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
chemical_list: D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D020932:Nerve Growth Factor; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases