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Molecular and Cellular Biology, June 2006, p. 4474-4488, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.01926-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factor ß-Induced Apoptosis

Takashi Yano,1,2 Kosei Ito,1,3 Hiroshi Fukamachi,4 Xin-Zi Chi,5 Hee-Jun Wee,1 Ken-ichi Inoue,1 Hiroshi Ida,1 Philippe Bouillet,6 Andreas Strasser,6 Suk-Chul Bae,5 and Yoshiaki Ito1,3*

Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore,1 Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,2 Oncology Research Institute, NUMI, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore,3 Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan,4 Department of Biochemistry, College of Medicine, Institute of Medical Research, Chungbuk National University, Cheongju 361-763, South Korea,5 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia6

Received 2 October 2005/ Returned for modification 4 December 2005/ Accepted 22 March 2006

Genes involved in the transforming growth factor ß (TGF-ß) signaling pathway are frequently altered in several types of cancers, and a gastric tumor suppressor RUNX3 appears to be an integral component of this pathway. We reported previously that apoptosis is notably reduced in Runx3–/– gastric epithelial cells. In the present study, we show that a proapoptotic gene Bim was transcriptionally activated by RUNX3 in the gastric cancer cell lines SNU16 and SNU719 treated with TGF-ß. The human Bim promoter contains RUNX sites, which are required for its activation. Furthermore, a dominant negative form of RUNX3 comprised of amino acids 1 to 187 increased tumorigenicity of SNU16 by inhibiting Bim expression. In Runx3–/– mouse gastric epithelium, Bim was down-regulated, and apoptosis was reduced to the same extent as that in Bim–/– gastric epithelium. We confirmed comparable expression of TGF-ß1 and TGF-ß receptors between wild-type and Runx3–/– gastric epithelia and reduction of Bim in TGF-ß1–/– stomach. These results demonstrate that RUNX3 is responsible for transcriptional up-regulation of Bim in TGF-ß-induced apoptosis.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore. Phone: 65 6586 9646. Fax: 65 6779 1117. E-mail: itoy{at}imcb.a-star.edu.sg.

Molecular and Cellular Biology, June 2006, p. 4474-4488, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.01926-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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