2011 Fiscal Year Final Research Report
To clarify the mechanism that C terminal fragments of EGFR ligand cause nuclear export of transcriptional repressors
| Project/Area Number |
21590790
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Nagoya City University |
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Principal Investigator |
JOH Takashi 名古屋市立大学, 大学院・医学研究科, 教授 (30231369)
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| Co-Investigator(Kenkyū-buntansha) |
KATAOKA Hiromi 名古屋市立大学, 大学院・医学研究科, 准教授 (40381785)
TANIDA Satoshi 名古屋市立大学, 大学院・医学研究科, 助教 (30528782)
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| Co-Investigator(Renkei-kenkyūsha) |
HIGASHIYAMA Shigeki 愛媛大学, 医学部, 教授 (60202272)
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| Project Period (FY) |
2009 – 2011
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| Keywords | HB-EGF shedding / ADAM / BCL6 / HB-EGF-CTF / 癌治療戦略 |
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| Research Abstract |
BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF(C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT. PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.
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Research Products
(14 results)
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[Journal Article] HB-EGF-C末端核移行シグナルをターゲットにした新規薬剤探索と細胞増殖抑制機序2011
Author(s)
尾関啓司, 谷田諭史, 溝下勤, 水島隆史, 志村貴也, 村上賢治, 平田慶和, 片岡洋望, 神谷武, 福田伸治, 東山繁樹, 城卓志
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Journal Title
消化器と免疫
Volume: 47
Pages: 144-146
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[Journal Article] TGFβinduces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancercells2010
Author(s)
Ebi M, Kataoka H, Shimura T, Kubota E, Hirata Y, Mizushima T, Mizoshita T, Tanaka M, Mabuchi M, Tsukamoto H, Tanida S, Kamiya T, Higashiyama S, Joh T
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Journal Title
Biochem Biophys Res Commun
Volume: 402(3)
Pages: 449-54
DOI
Peer Reviewed
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[Journal Article] BCL6 degradation caused by the interation with the C-terminus of proHB-EGF induces cycline D2 expression in gastric cancers2009
Author(s)
Hirata Y, Ogasawara N, Sasaki M, Mizushima T, Mizoshita T, Shimura T, Mori Y, Kubota E, Wada T, Tanida S, Kataoka H, Kamiya T, Higashiyama S, Joh T
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Journal Title
British Journal of Cancer
Volume: 100
Pages: 1320-1329
DOI
Peer Reviewed
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