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J. Biol. Chem., Vol. 281, Issue 11, 7384-7391, March 17, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/11/7384    most recent M509876200v1 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 Wang, D. Articles by Yodoi, J. Search for Related Content PubMed PubMed Citation Articles by Wang, D. Articles by Yodoi, J. Social Bookmarking                      What's this?

Control of Mitochondrial Outer Membrane Permeabilization and Bcl-xL Levels by Thioredoxin 2 in DT40 Cells^*

Dongmei Wang¹, Hiroshi Masutani², Shin-ichi Oka, Toru Tanaka, Yuko Yamaguchi-Iwai, Hajime Nakamura^¶, and Junji Yodoi

From the Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo, Kyoto 606-8507, the Department of Applied Molecular Bioloy, Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo, Kyoto 606-8502, and the ^¶Translational Research Center, Kyoto University Hospital, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan

Mitochondria play a central role in the initiation of apoptosis, which is regulated by various factors such as ATP synthesis, reactive oxygen species, redox status, and outer membrane permeabilization. Disruption of chicken thioredoxin 2 (Trx2), a mitochondrial redox-regulating protein, results in apoptosis in DT40 cells. To investigate the mechanism of this apoptosis, we prepared transfectants expressing control (DT40-TRX2-/-), human thioredoxin 2 (TRX2) (DT40-hTRX2), or redox-inactive TRX2 (DT40-hTRX2CS) in conditional Trx2-deficient DT40 cells containing a tetracycline-repressible Trx2 gene. Production of ATP was not significantly changed by down-regulation of Trx2 expression. The generation of reactive oxygen species was enhanced by the down-regulation of Trx2 expression in DT40-TRX2-/-. Unexpectedly, the change was blocked in both DT40-hTRX2 and DT40-hTRX2CS cells. The down-regulation of Trx2 expression caused the release of cytochrome c and apoptosis-inducing factor on day 3, and apoptosis on day 5. These changes were also suppressed in both DT40-hTRX2 and DT40-hTRX2CS cells, suggesting that TRX2 regulates mitochondrial outer membrane permeabilization and apoptosis by redox-active site cysteine-independent mechanisms. The down-regulation of Trx2 expression caused a decrease in the protein level of Bcl-xL on day 3, whereas the protein level of Bcl-2 did not change until day 4, and the mRNA level of Bcl-xL was unchanged. The decrease in Bcl-xL was not blocked by a caspase 3 inhibitor but blocked in both DT40-hTRX2 and DT40-hTRX2CS. These findings indicate a link between the redox active site cysteine-independent action of TRX2 and the level of Bcl-xL in the regulation of apoptosis.

Received for publication, September 7, 2005 , and in revised form, January 5, 2006.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant-in-aid from the Research and Development Program for New Bio-industry Initiatives. 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 Fig. S1.

¹ Supported by the 21st Century COE Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² To whom correspondence should be addressed. Tel.: 81-75-751-4026; Fax: 81-75-761-5766; E-mail: hmasutan{at}virus.kyoto-u.ac.jp.

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