RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD.
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.
Chi
Xin-Zi
XZ
Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Yang
Jeung-Ook
JO
Lee
Kwang-Youl
KY
Ito
Kosei
K
Sakakura
Chohei
C
Li
Qing-Lin
QL
Kim
Hye-Ryun
HR
Cha
Eun-Jeung
EJ
Lee
Yong-Hee
YH
Kaneda
Atsushi
A
Ushijima
Toshikazu
T
Kim
Wun-Jae
WJ
Ito
Yoshiaki
Y
Bae
Suk-Chul
SC
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
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