title: RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD.
abstract: 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 beta1 (TGF-beta1). It is known that TGF-beta1 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-beta-dependent induction of p21 expression in stomach epithelial cells. Overexpression of RUNX3 potentiates TGF-beta-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.
authors.affiliation: Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
authors.forename: Xin-Zi
authors.initials: XZ
authors.lastname: Chi
authors.forename: Jeung-Ook
authors.initials: JO
authors.lastname: Yang
authors.forename: Kwang-Youl
authors.initials: KY
authors.lastname: Lee
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Chohei
authors.initials: C
authors.lastname: Sakakura
authors.forename: Qing-Lin
authors.initials: QL
authors.lastname: Li
authors.forename: Hye-Ryun
authors.initials: HR
authors.lastname: Kim
authors.forename: Eun-Jeung
authors.initials: EJ
authors.lastname: Cha
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Lee
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Suk-Chul
authors.initials: SC
authors.lastname: Bae
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D050677:Core Binding Factor Alpha 3 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051785:Smad Proteins; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; D051785:Smad Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins