title: Rapid and long-lasting suppression of the ATF-2 transcription factor is a common response to neuronal injury.
abstract: The activating transcription factor 2 (ATF-2) protein, a neuronal constitutively expressed CRE-binding transcription factor, is essential for the intact development of the mammalian brain. ATF-2 is activated by c-Jun N-terminal kinases and modulates both the induction of the c-jun gene and the function of the c-Jun protein, a mediator of neuronal death and survival. Here we show by immunocytochemistry and Western blotting that ATF-2 is rapidly suppressed in neurons within 1-4 h following neuronal stress such as transient focal ischemia by occlusion of the medial cerebral artery, mechanical injury of the neuroparenchym, stimulation of adult dorsal root ganglion neurons in vitro by doxorubicin as well as within 24 h following nerve fiber transection. ATF-2 reappears and regains basal levels between 12 h and 72 h following ischemia, between 50 and 100 days following axotomy, but remains absent around the site of mechanical injury during the process of degeneration. Following ischemia and tissue injury, ATF-2-IR also disappeared in areas remote from the affected brain compartments indicating the regulation of its expression by diffusible molecules. These findings demonstrate that the rapid and persistent down-regulation of ATF-2 is a constituent of the long-term neuronal stress response and that the reappearance of ATF-2 after weeks is a marker for the normalization of neuronal gene transcription following brain injury.
authors.affiliation: Institute of Physiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Martin-Villalba
authors.forename: C
authors.initials: C
authors.lastname: Winter
authors.forename: S
authors.initials: S
authors.lastname: Brecht
authors.forename: T
authors.initials: T
authors.lastname: Buschmann
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: T
authors.initials: T
authors.lastname: Herdegen
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D019771:Axotomy; D001930:Brain Injuries / Q000235:genetics* / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity; D020220:Facial Nerve Injuries; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009409:Nerve Crush; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000293:injuries; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D004317:Doxorubicin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases