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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>
Causal relationship between the loss of RUNX3 expression and gastric cancer
Qing-Lin Li,Chohei Sakakura,Kosei Ito,Xin-Zi Chi,Lee, Kwang-Youl,Lee, Chang-Woo,Han, Sang-Bae,Kim, Hwan-Mook,Kim, Wun-Jae,Atsushi Kaneda,Toshikazu Ushijima,Yoshiaki Ito,Bae, Suk-Chul 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
The human runt-related gene RUNX3/PEBP2αC, located on chromosome 1p36, is a major mediator of signals elicited by members of the transforming growth factor-β(TGF-β) superfamily. Here we show that 45-60% of gastric cancer cell lines and surgically resected specimens do not significantly express RUNX3 due to a combination of hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and one gastric tumor associated mutation(R122C), occurring within the conserved Runt domain completely abolished the tumor suppressive effect of RUNX3. The results suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.
E1A physically interacts with RUNX3 and inhibits its transactivation activity
Cha, Eun‐,Jeong,Oh, Byung‐,Chul,Wee, Hee‐,Jun,Chi, Xin‐,Zi,Goh, Yun‐,Mi,Lee, Kyeong‐,Sook,Ito, Yoshiaki,Bae, Suk‐,Chul Wiley Subscription Services, Inc., A Wiley Company 2008 Journal of cellular biochemistry Vol.105 No.1
<P><B>Abstract</B></P><P>The adenoviral gene, termed <I>early region 1A</I> (<I>E1A</I>), is crucial for transformation and has been used very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. pRb, p107, p130, p300/CBP, p400, TRRAP, and CtBP were identified to be E1A‐binding proteins and their roles in cellular transformation have been established. Although the major function of E1A is considered to be the regulation of gene expression that is critical for differentiation and cell cycle exit, one of the most significant questions relating to E1A transformation is how E1A mediates this regulation. RUNX3 is a transcription factor that was first described as a gastric cancer tumor suppressor but is now known to be involved in many different cancers. Exogenous expression of <I>RUNX3</I> strongly inhibits the growth of cells. Here, we show that the adenovirus oncoprotein E1A interacts with RUNX3 in vitro and in vivo. RUNX3 interacts with the N‐terminus (amino acids 2‐29) of E1A, which is known to interact with p300/CBP, p400, and TRRAP. E1A interacts directly with the Runt domain of RUNX3 but does not interfere with CBFβ‐RUNX3 interactions. In addition, E1A inhibits the transactivation activity of RUNX3 on the <I>p21</I><SUP><I>WAF1/CIP1</I></SUP> promoter. Consistent with these observations, the growth inhibition induced by RUNX3 is reduced by E1A. These results demonstrate that E1A specifically binds to RUNX3 and inactivates its transactivation activity. We propose that one of the mechanisms for the oncogenic activity of E1A is the inhibition of RUNX3, similar to that of RB and p300/CBP. J. Cell. Biochem. 105: 236–244, 2008. © 2008 Wiley‐Liss, Inc.</P>
이유섭,Ja-Yeol Lee,Soo-Hyun Song,Da-Mi Kim,Jung-Won Lee,Xin-Zi Chi,Yoshiaki Ito,배석철 한국분자세포생물학회 2020 Molecules and cells Vol.43 No.10
K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-RAS mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a significant impact on early K-RAS–induced lung tumorigenesis. These results raise the question of how K-RAS–activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14ARF–p53 pathway. In this study, we found that K-RAS activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and K-RAS was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of K-RAS–driven human lung tumors, Runx3 was inactivated in both adenomas (ADs) and ADCs, whereas K-RAS was activated only in ADCs. Together, these results demonstrate that the R-point–associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against K-RAS activation, resulting in the transition from AD to ADC. Therefore, K-RAS–activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which Runx3 has been inactivated.
Src Kinase Phosphorylates RUNX3 at Tyrosine Residues and Localizes the Protein in the Cytoplasm
Goh, Yun-Mi,Cinghu, Senthilkumar,Hong, Eileen Tan Hwee,Lee, You-Soub,Kim, Jang-Hyun,Jang, Ju-Won,Li, Ying-Hui,Chi, Xin-Zi,Lee, Kyeong-Sook,Wee, Heejun,Ito, Yoshiaki,Oh, Byung-Chul,Bae, Suk-Chul American Society for Biochemistry and Molecular Bi 2010 The Journal of biological chemistry Vol.285 No.13
<P>RUNX3 is a transcription factor that functions as a tumor suppressor. In some cancers, <I>RUNX3</I> expression is down-regulated, usually due to promoter hypermethylation. Recently, it was found that RUNX3 can also be inactivated by the mislocalization of the protein in the cytoplasm. The molecular mechanisms controlling this mislocalization are poorly understood. In this study, we found that the overexpression of Src results in the tyrosine phosphorylation and cytoplasmic localization of RUNX3. We also found that the tyrosine residues of endogenous RUNX3 are phosphorylated and that the protein is localized in the cytoplasm in Src-activated cancer cell lines. We further showed that the knockdown of <I>Src</I> by small interfering RNA, or the inhibition of Src kinase activity by a chemical inhibitor, causes the re-localization of RUNX3 to the nucleus. Collectively, our results demonstrate that the tyrosine phosphorylation of RUNX3 by activated Src is associated with the cytoplasmic localization of RUNX3 in gastric and breast cancers.</P>
Jab1/CSN5 induces the cytoplasmic localization and degradation of RUNX3
Kim, Jang-Hyun,Choi, Joong-Kook,Cinghu, Senthilkumar,Jang, Ju-Won,Lee, You-Soub,Li, Ying-Hui,Goh, Yun-Mi,Chi, Xin-Zi,Lee, Kyeong-Sook,Wee, Heejun,Bae, Suk-Chul Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of cellular biochemistry Vol.107 No.3
<P>Runt-related (RUNX) transcription factors play pivotal roles in neoplastic development and have tissue-specific developmental roles in hematopoiesis (RUNX1), osteogenesis (RUNX2), as well as neurogenesis and thymopoiesis (RUNX3). RUNX3 is a tumor suppressor in gastric carcinoma, and its expression is frequently inactivated by DNA methylation or its protein mislocalized in many cancer types, including gastric and breast cancer. Jun-activation domain-binding protein 1 (Jab1/CSN5), a component of the COP9 signalosome (CSN), is critical for nuclear export and the degradation of several tumor suppressor proteins, including p53, p27<SUP>Kip1</SUP>, and Smad4. Here, we find that Jab1 facilitates nuclear export of RUNX3 that is controlled by CSN-associated kinases. RUNX3 sequestered in the cytoplasm is rapidly degraded through a proteasome-mediated pathway. Our results identify a novel mechanism of regulating nuclear export and protein stability of RUNX3 by the CSN complex. J. Cell. Biochem. 107: 557–565, 2009. © 2009 Wiley-Liss, Inc.</P>
The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1
Suk-Chul Bae,Jung-Won Lee,Min-Kyu Kim,Sang-Hyun Han,Tae-Geun Park,Soo-Hyun Song,Ja-Youl Lee,이유섭,Seo-Yeong Yoo,Xin-Zi Chi,김응국,Ju-Won Jang,임대식,Andre J. van Wijnen 한국분자세포생물학회 2023 Molecules and cells Vol.46 No.10
The Hippo kinase cascade functions as a central hub that relays input from the “outside world” of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.