title: Neuronal injury-inducible gene is synergistically regulated by ATF3, c-Jun, and STAT3 through the interaction with Sp1 in damaged neurons.
abstract: Nerve injury requires the expression of large ensembles of genes. The key molecular mechanism for this gene transcription regulation in injured neurons is poorly understood. Among many nerve injury-inducible genes, the gene encoding damage-induced neuronal endopeptidase (DINE) showed most marked expression response to various kinds of nerve injuries in central and peripheral nervous system neurons. This unique feature led us to examine the promoter region of the DINE gene and clarify both the injury-responsive element within the promoter and its related transcriptional machinery. This study showed that DINE promoter was activated by leukemia inhibitory factor and nerve growth factor withdrawal, which were pivotal for the up-regulation of DINE mRNA after nerve injury. The injury-inducible transcription factors such as activating transcription factor 3 (ATF3), c-Jun, and STAT3, which were located at the downstream of leukemia inhibitory factor and nerve growth factor withdrawal, seemed to be involved in the activation of the DINE promoter. Surprisingly, these transcription factors did not bind to the DINE promoter directly. Instead, the general transcription factor, Sp1, bound to a GC box within the promoter. ATF3, c-Jun, and STAT3 interacted with Sp1 and are associated with the GC box region of the DINE gene in injured neurons. These findings suggested that Sp1 recruit ATF3, c-Jun, and STAT3 to obtain the requisite synergistic effect. Of these transcription factors, ATF3 may be the most critical, because ATF3 is specifically expressed after nerve injury.
authors.affiliation: Department of Anatomy and Neurobiology, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Kiryu-Seo
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kato
authors.forename: Tokiko
authors.initials: T
authors.lastname: Ogawa
authors.forename: Saya
authors.initials: S
authors.lastname: Nakagomi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyama
mesh_terms: D051700:Activating Transcription Factor 3 / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497108:Atf3 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016329:Sp1 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D008666:Metalloendopeptidases; C407822:damage-induced neuronal endopeptidase