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J. Biol. Chem., Vol. 283, Issue 11, 6988-6996, March 14, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/11/6988    most recent M707514200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kiryu-Seo, S. Articles by Kiyama, H. PubMed PubMed Citation Articles by Kiryu-Seo, S. Articles by Kiyama, H. Social Bookmarking                      What's this?

Neuronal Injury-inducible Gene Is Synergistically Regulated by ATF3, c-Jun, and STAT3 through the Interaction with Sp1 in Damaged Neurons^*

From the Department of Anatomy and Neurobiology, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan

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.

Received for publication, September 7, 2007 , and in revised form, December 28, 2007.

^* This work was supported by grants from Ministry of Health, Labor and Welfare of Japan, Ministry of Education, Culture, Sports, Science and Technology (MEXT), The Ichiro Kanehara Foundation, Senri Life Science Foundation, and Japan Brain Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 81-6-6645-3701; Fax: 81-6-6645-3702; E-mail: kiyama{at}med.osaka-cu.ac.jp.

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