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

Abstract

Genes involved in the transforming growth factor β (TGF-β) 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-β. 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-β1 and TGF-β receptors between wild-type and Runx3^−/− gastric epithelia and reduction of Bim in TGF-β1^−/− stomach. These results demonstrate that RUNX3 is responsible for transcriptional up-regulation of Bim in TGF-β-induced apoptosis.

We thank S. Yonehara for critical reading of the manuscript and for helpful discussion. We also thank Y. K. Loh, E. Tai, and the staff in the animal holding unit in IMCB for their technical help.

This work was supported by A*STAR (Agency for Science, Technology and Research), Singapore and Human Frontier Science Program, RGP0375/2001-M202.