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Chi, Xin-Zi,Yang, Jeung-Ook,Lee, Kwang-Youl,Ito, Kosei,Sakakura, Chohei,Li, Qing-Lin,Kim, Hye-Ryun,Cha, Eun-Jeung,Lee, Yong-Hee,Kaneda, Atsushi,Ushijima, Toshikazu,Kim, Wun-Jae,Ito, Yoshiaki,Bae, Suk- American Society for Microbiology 2005 Molecular and cellular biology Vol.25 No.18
<B>ABSTRACT</B><P><I>RUNX3</I> has been suggested to be a tumor suppressor of gastric cancer. The gastric mucosa of the <I>Runx3</I>-null mouse develops hyperplasia due to enhanced proliferation and suppressed apoptosis accompanied by a decreased sensitivity to transforming growth factor β1 (TGF-β1). It is known that TGF-β1 induces cell growth arrest by activating <I>CDKN1A</I> (<I>p21</I><SUP><I>WAF1</I></SUP><SUP>/<I>Cip1</I></SUP>), 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 <I>p21</I> expression is not known. Here we show that <I>RUNX3</I> is required for the TGF-β-dependent induction of <I>p21</I> expression in stomach epithelial cells. Overexpression of <I>RUNX3</I> potentiates TGF-β-dependent endogenous <I>p21</I> induction. In cooperation with SMADs, RUNX3 synergistically activates the <I>p21</I> promoter. In contrast, <I>RUNX3</I>-<I>R122C</I>, a mutation identified in a gastric cancer patient, abolished the ability to activate the <I>p21</I> promoter or cooperate with SMADs. Furthermore, areas in mouse and human gastric epithelium where <I>RUNX3</I> is expressed coincided with those where <I>p21</I> is expressed. Our results suggest that at least part of the tumor suppressor activity of <I>RUNX3</I> is associated with its ability to induce <I>p21</I> expression.</P>