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J. Biol. Chem., Vol. 280, Issue 30, 27638-27644, July 29, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/30/27638    most recent M501304200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsujimoto, K. Articles by Tadakuma, T. Search for Related Content PubMed PubMed Citation Articles by Tsujimoto, K. Articles by Tadakuma, T. Social Bookmarking                      What's this?

Regulation of the Expression of Caspase-9 by the Transcription Factor Activator Protein-4 in Glucocorticoid-induced Apoptosis^*

Kyoko Tsujimoto, Takeshi Ono, Masaki Sato, Takashi Nishida, Takemi Oguma, and Takushi Tadakuma

From the Department of Parasitology and Immunology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan

Caspase-9 (Casp-9) induces death signals by triggering other types of caspase activation, and its expression greatly influences the onset of apoptosis. During the isolation of apoptosis-related genes involved in glucocorticoid (GC)-induced cell death in murine thymic lymphomas, we found that the antisense gene of the transcription factor activator protein-4 (AP-4) inhibited dexamethasone-induced apoptosis. Western blot analysis revealed that the expression of Bcl-x_L, Bax, and Apaf-1 was not affected in cells transfected with sense or antisense AP-4 genes. In contrast, both the expression and activation of Casp-9 were inhibited in the antisense AP-4 transfectants. We isolated the 2.4-kb 5'-flanking region of Casp-9, and the promoter activity was investigated. We found the AP-4-binding sites at –1.55 and –1.38 kb to be responsible for the promoter activity. Furthermore, a negative cis-element was expected to exist between bases –1140 and –944. When the cells were treated with dexamethasone, a rapid down-regulation of AP-4 and Casp-9 was observed whether the cells were GC-sensitive lymphomas or GC-insensitive L929 fibroblast cells. In addition, L929 cells pretreated with dexamethasone were found to be resistant to subsequent treatment with etoposide, an apoptosis-inducing reagent. GC has a two-sided effect on apoptosis, i.e. a pro-apoptotic effect on certain cell types and a prosurvival effect on other cell types. Our findings will explain, at least in part, this effect.

Received for publication, February 3, 2005 , and in revised form, May 24, 2005.

^* 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 Fig. 1.

To whom correspondence should be addressed. Tel.: 81-4-2995-1576; Fax: 81-4-2996-5197; E-mail: tadakuma{at}ndmc.ac.jp.

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