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RUNX3 Suppresses Gastric Epithelial Cell Growth by Inducing p21^WAF1/Cip1 Expression in Cooperation with Transforming Growth Factor ß-Activated SMAD

Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea,¹ Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore,² Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Kamigyo-ku, Kyoto 602-0841, Japan,³ National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan,⁴ Department of Urology, School of Medicine, Chungbuk National University, Cheongju 361-763, South Korea⁵

Received 25 February 2005/ Returned for modification 8 April 2005/ Accepted 18 June 2005

RUNX3 has been suggested to be a tumor suppressor of gastric cancer. The gastric mucosa of the Runx3-null mouse develops hyperplasia due to enhanced proliferation and suppressed apoptosis accompanied by a decreased sensitivity to transforming growth factor ß1 (TGF-ß1). It is known that TGF-ß1 induces cell growth arrest by activating CDKN1A (p21^WAF1/Cip1), which encodes a cyclin-dependent kinase inhibitor, and this signaling cascade is considered to be a tumor suppressor pathway. However, the lineage-specific transcription factor that cooperates with SMADs to induce p21 expression is not known. Here we show that RUNX3 is required for the TGF-ß-dependent induction of p21 expression in stomach epithelial cells. Overexpression of RUNX3 potentiates TGF-ß-dependent endogenous p21 induction. In cooperation with SMADs, RUNX3 synergistically activates the p21 promoter. In contrast, RUNX3-R122C, a mutation identified in a gastric cancer patient, abolished the ability to activate the p21 promoter or cooperate with SMADs. Furthermore, areas in mouse and human gastric epithelium where RUNX3 is expressed coincided with those where p21 is expressed. Our results suggest that at least part of the tumor suppressor activity of RUNX3 is associated with its ability to induce p21 expression.

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