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Oncogenic RUNX3: A Link between p53 Deficiency and MYC Dysregulation
Date, Yuki,Ito, Kosei Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.2
The RUNX transcription factors serve as master regulators of development and are frequently dysregulated in human cancers. Among the three family members, RUNX3 is the least studied, and has long been considered to be a tumor-suppressor gene in human cancers. This idea is mainly based on the observation that RUNX3 is inactivated by genetic/epigenetic alterations or protein mislocalization during the initiation of tumorigenesis. Recently, this paradigm has been challenged, as several lines of evidence have shown that RUNX3 is upregulated over the course of tumor development. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. We propose a simple explanation for the duality of RUNX3: p53 status. In this model, p53 deficiency causes RUNX3 to become an oncogene, resulting in aberrant upregulation of MYC.
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.
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
Bae, Suk-Chul,Qing-Lin Li,Chohei Sakakura,Kosei Ito,Kim, Hwan-Mook,Yoshiaki Ito 이화여자대학교 세포신호전달연구센터 2003 고사리 세포신호전달 심포지움 Vol. No.5
The mammalian runt-related(RUNX) genes encode the α subunit of the Runt domain transcription factor PEBP2/CBF and are homologues of the Drosophila genes runt and lozenge. The mammalian and Drosophila genes share an evolutionarily conserved region of 128 amino acids, termed the Runt domain, which is required for DNA binding and heterodimerization with the β subunit, PEBP2β/CBF. Like their Drosophila homologues, the RUNX family proteins are critical regulators in determining cell fate. Three RUNX genes, RUNX1 AML1, RUNX2/CBFA1 and RUNX3/PEBP2αC, are known. RUNX1 has a critical role in the formation of hematopoietic stem cells from hematogenic endothelial cells. RUNX3 is expressed by the epithelial cells of the mouse glandular stomach and intestines. The runt homologue in C. elegan, run, is also expressed by gut cells, suggesting possible evolutionarily· conserved roles of runt homologues in the gastrointestinal tract. The major upstream regulatory signal of the RUNX family is elicited by the TGF-β superfamily. The functional relationship between the BMP signaling pathway and the RUNX protein was shown in a report that cleidocranial dysplasia is caused by an inability of mutated RUNX2 to transmit BMP signaling to target genes. Several lines of evidence suggest the possibility that RUNX3 is involved in gastric carcinogenesis. First, RUNX3 is located on human chromosome, one of the regions that shows high-frequency loss of heterozygosity(LOH) in gastric cancer. Second, it is well known that the TGF-β signal transduction system is often impaired in many different types of cancer. For example, the TGF-β type Ⅱ receptor is disrupted in colon cancer, gastric cancer, and head and neck cancers. Since RUNX3 is a downstream target of TGF-β signaling, malfunction of RUNX3 might be involved in gastric carcinogenesis. It has recently been suggested that escape from apoptosis is the most important characteristic of cancers in the gastrointestinal tract, and most, if not all, cancers, display insensitivity to anti-growth signals and evasion of apoptosis. This line of evidence suggests that RUNX3 is an attractive candidate as a tumor suppressor of gastric cancer. Here we show that RUNX3 possesses a potent anti-oncogenic activity and is frequently inactivated in gastric cancers by hemizygous deletion and hypermethylation of its promoter region. Although rare, we also found a single mutation(R122C) in the highly conserved Runt domain of RUNX3. This mutation leads to the complete loss of the anti-oncogenic activity in a nude mouse assay. These results strongly suggest that RUNX3 is a tumor suppressor widely involved in gastric cancer.