RAPID AND LONG-LASTING SUPPRESSION OF THE ATF-2 TRANSCRIPTION FACTOR IS A COMMON RESPONSE TO NEURONAL INJURY

The activating transcription factor 2 (ATF-2) protein, a neuronal cons titutively expressed CRE-binding transcription factor, is essential fo r 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-ju n gene and the function of the c-Jun protein, a mediator of neuronal d eath and survival. Here we show by immunocytochemistry and Western blo tting that ATF-2 is rapidly suppressed in neurons within 1-4 h followi ng neuronal stress such as transient focal ischemia by occlusion of th e medial cerebral artery, mechanical injury of the neuroparenchym, sti mulation of adult dorsal root ganglion neurons in vitro by doxorubicin as well as within 24 h following nerve fiber transection. ATF-2 reapp ears 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. Fol lowing 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 constituen t of the long-term neuronal stress response and that the reappearance of ATF-2 after weeks is a marker for the normalization of neuronal gen e transcription following brain injury. (C) 1998 Elsevier Science B.V. All rights reserved.