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J. Biol. Chem., Vol. 281, Issue 8, 5267-5276, February 24, 2006

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RUNX3 Cooperates with FoxO3a to Induce Apoptosis in Gastric Cancer Cells^*

Yasuko Yamamura, Wei Lin Lee^¶, Ken-ichi Inoue, Hiroshi Ida, and Yoshiaki Ito^¶1

From the Oncology Research Institute, National University Medical Institutes, Institute of Molecular and Cell Biology, ^¶Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117592, Singapore

The transcription factor RUNX3, which mediates apoptosis and cell growth inhibition in gastric epithelial cells, is a candidate tumor suppressor that is frequently lost in gastric cancer cells. Here, we found that restoration of RUNX3 expression in the cell line not expressing RUNX3 induced apoptosis and that it physically interacted with the Forkhead transcription factor FoxO3a/FKHRL1, known to be an important regulator of apoptosis and the cell cycle. Active unphosphorylated FoxO3a/FKHRL1 was expressed in the gastric cancer cell lines. RUNX3-induced apoptosis depended on the expression of Bim, a proapoptotic BH3-only protein, and both RUNX3 and FoxO3a/FKHRL1 were required for induction of Bim expression. Furthermore, we showed that interaction of RUNX3 and FoxO3a/FKHRL1 was also indispensable for Bim expression and apoptosis in mouse embryonic fibroblasts. In the Bim promoter, RUNX3 bound to two conserved RUNX-binding elements (RBE1 and RBE2), with RBE1 being immediately downstream of a FoxO-binding element. The physical interaction of RUNX3 and FoxO3a/FKHRL1 on the Bim promoter activated transcription of Bim. These findings show that RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim and may play an important role in tumor suppression in gastric cancer.

Received for publication, November 11, 2005 , and in revised form, December 20, 2005.

^* This work was supported in part by a Research Grant, Academic Research Fund, National University of Singapore (NUS-R-364-000-025-112 (to Y. Y.)) and an Individual Research Grant, National Medical Research Council, Singapore (NMRC-R-364-000-036-213 (to Y. Y.)). 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. S1.

¹ To whom correspondence should be addressed: Oncology Research Inst., National University Medical Insts., National University of Singapore, Clinical Research Centre, Block MD11, Level 5, 10 Medical Dr., Singapore 117592, Singapore. Tel.: 65-6586-9646; Fax: 65-6873-9664; E-mail: itoy{at}imcb.a-star.edu.sg.

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