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J. Biol. Chem., Vol. 281, Issue 3, 1620-1629, January 20, 2006

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A Splice Variant of Stress Response Gene ATF3 Counteracts NF-B-dependent Anti-apoptosis through Inhibiting Recruitment of CREB-binding Protein/p300 Coactivator^*

From the Department of Biochemical Genetics, Medical Research Institute, and Laboratory of Genome Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Activating transcription factor (ATF) 3 plays a role in determining cell fate and generates a variety of alternatively spliced isoforms in stress response. We have reported previously that splice variant ATF3Zip2, which lacks the leucine zipper region, is induced in response to various stress stimuli. However, its biological function has not been elucidated. By using cells treated with tumor necrosis factor- and actinomycin D or cells overexpressing ATF3Zip2, we showed that ATF3Zip2 sensitizes cells to apoptotic cell death in response to tumor necrosis factor-, at least in part through suppressing nuclear factor (NF)-B-dependent transcription of anti-apoptotic genes such as cIAP2 and XIAP. ATF3Zip2 interacts with a p65 (RelA)-cofactor complex containing CBP/p300 and HDAC1 at NF-B sites of the proximal promoter region of the cIAP2 gene in vivo and down-regulates the recruitment of CBP/p300. Our study revealed that ATF3Zip2 counteracts anti-apoptotic activity of NF-B, at least in part, by displacing positive cofactor CBP/p300 and provides insight into the mechanism by which ATF3 regulates cell fate through alternative splicing in stress response.

Received for publication, August 2, 2005 , and in revised form, October 17, 2005.

^* This work was supported in part by a grant-in-aid for research on priority areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to S. K.). 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.

¹ Present address: Research Center for Medical Genomics and Key Laboratory of Cell Biology, Ministry of Health, China Medical University, Shenyang 110001, China.

² To whom correspondence should be addressed: Dept. of Biochemical Genetics, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. Tel.: 81-3-5803-5822; Fax: 81-3-5803-0248; E-mail: kita.bgen{at}mri.tmd.ac.jp.

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