Elucidation of the roles of the Hippo-YAP signaling pathway in regulating cell tension in liver development and regeneration
Project/Area Number |
20H03381
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Nishina Hiroshi 東京医科歯科大学, 難治疾患研究所, 教授 (60212122)
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Co-Investigator(Kenkyū-buntansha) |
小藤 智史 東京医科歯科大学, 難治疾患研究所, 講師 (00508153)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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Keywords | 肝臓 / 細胞排除 / 細胞間張力 / YAP / Hippoシグナル / サイズ / 細胞張力 / 肝発生 / 肝再生 / MDCK細胞 / Hippo-YAP / FRET |
Outline of Research at the Start |
本研究では、肝臓の三次元(3D)器官形成のメカニズムを、Hippo-YAPシグナル伝達経路や細胞張力の観点から解明することを目的とする。課題1:肝臓特異的にYAPとそのパラログTAZを欠損するマウスを作出し、細胞張力制御の観点から、肝発生および肝再生におけるYAP/TAZの役割を解析する。課題2:実績のある張力バイオセンサーをメダカの全身および肝臓特異的に発現し、細胞張力を可視化し、細胞張力マップを作成する。また、hirame 変異体の細胞張力も本張力バイオセンサーで解析する。
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Outline of Final Research Achievements |
The liver forms three-dimensional (3D) structures of a certain size through cell proliferation and cell differentiation. We have isolated a medaka mutant in which tissues including epithelium become flattened, and analysis of this mutant revealed that the transcriptional co-activator YAP plays an essential role in 3D organogenesis via cell tension. We also found that overexpression of YAP in canine renal epithelial cells MDCK induced pressure in neighboring cells and pushed YAP-expressing cells to the apical surface. Therefore, we attempted to visualize the physical forces by utilizing a FRET probe (mCherry-spider silk protein-EGFP containing the basic structure). We found that FRET was induced between two MDCK cells in a time-dependent manner. Thus these results indicate the existence of the pressure generated between two cells to be eliminated.
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Academic Significance and Societal Importance of the Research Achievements |
転写共役因子YAPは様々ながんの発症や悪性化に関与することが指摘されているが、その分子機構については不明な点が多い。実際、ヒト癌においてYAP遺伝子変異の報告は多くなく、どのように病態に関与しているかは国内外を通じて課題となっている。本研究成果から、この理由の一つとして、これまでの細胞生物学では検出が困難であった細胞間張力の制御が考えられる。すなわち、YAP依存性の細胞間張力制御機構の解明は発がん機構の解明の一端を解明に貢献すると期待される。
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Report
(4 results)
Research Products
(27 results)
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[Journal Article] Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers.2022
Author(s)
Soyama H, Nishio M, Otani J, Sakuma T, Takao S, Hara S, Masuda T, Mimori K, Toyokuni S, Lydon JP, Nakao K, Nishina H, Fukumoto T, Maehama T, Suzuki A.
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Journal Title
Proc Natl Acad Sci U S A
Volume: 119
Issue: 29
Pages: 1-10
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Abnormal male reproduction and embryonic development induced by downregulation of a phospholipid fatty acid-introducing enzyme Lpgat1 in zebrafish2022
Author(s)
Shibata T, Kawana H, Nishino Y, Ito Y, Sato H, Onishi H, Kano K, Inoue A, Taketomi Y, Murakami M, Kofuji S, Nishina H, Miyazawa A, Kono N, Aoki J.
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Journal Title
Scientific reports
Volume: 12
Issue: 1
Pages: 7312-7312
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation2022
Author(s)
Kobayashi S, Ogasawara N, Watanabe S, Yoneyama Y, Kirino S, Hiraguri Y, Inoue M, Nagata S, Okamoto-Uchida Y, Kofuji S, Shimizu H, Ito G, Mizutani T, Yamauchi S, Kinugasa Y, Kano Y, Nemoto Y, Watanabe M, Tsuchiya K, Nishina H, Okamoto R, Yui S.
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Journal Title
Inflammation and Regeneration
Volume: 42
Issue: 1
Pages: 49-49
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] CSE1L promotes nuclear accumulation of transcriptional coactivator TAZ and enhances invasiveness of human cancer cells.2021
Author(s)
Nagashima S, Maruyama J, Honda K, Kondoh Y, Osada H, Nawa M, Nakahama KI, Ishigami-Yuasa M, Kagechika H, Sugimura H, Iwasa H, Arimoto-Matsuzaki K, Nishina H, Hata Y
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Journal Title
Journal of Biological Chemistry
Volume: 297
Issue: 1
Pages: 100803-100803
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.2021
Author(s)
Nakatani K, Maehama T, Nishio M, Otani J, Yamaguchi K, Fukumoto M, Hikasa H, Hagiwara S, Nishina H, Mak TW, Honma T, Kondoh Y, Osada H, Yoshida M, Suzuki A
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Journal Title
Cancer Science
Volume: 112
Issue: 10
Pages: 4303-4316
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition.2020
Author(s)
Ishihara E, Nagaoka Y, Okuno T, Kofuji S, Ishigami-Yuasa M, Kagechika H, Kamimura K, Terai S, Yokomizo T, Sugimoto Y, Fujita Y, Suzuki A, Nishina H.
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Journal Title
Genes Cells.
Volume: 25(3)
Issue: 3
Pages: 197-214
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.2020
Author(s)
Miki Nishio , Yoko To , Tomohiko Maehama , Yukari Aono , Junji Otani , Hiroki Hikasa , Akihiro Kitagawa , Koshi Mimori , Takehiko Sasaki , Hiroshi Nishina , Shinya Toyokuni , John P Lydon , Kazuwa Nakao , Tak Wah Mak , Tohru Kiyono , Hidetaka Katabuchi , Hironori Tashiro , Akira Suzuki
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Journal Title
Cancer science
Volume: 111
Issue: 10
Pages: 3576-3578
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing.2020
Author(s)
Hanzawa N, Hashimoto K, Yuan X, Kawahori K, Tsujimoto K, Hamaguchi M, Tanaka T, Nagaoka Y, Nishina H, Morita S, Hatada I, Yamada T, Ogawa Y.
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Journal Title
Sci Rep.
Volume: 10
Issue: 1
Pages: 5181-5181
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Characterization of a novel compound that promotes myogenesis via Akt and transcriptional co-activator with PDZ-binding motif (TAZ) in mouse C2C12 cells.2020
Author(s)
Kodaka M, Mao F, Arimoto-Matsuzaki K, Kitamura M, Xu X, Yang Z, Nakagawa K, Maruyama J, Ishii K, Akazawa C, Oyaizu T, Yamamoto N, Ishigami-Yuasa M, Tsuemoto N, Ito S, Kagechika H, Nishina H, Hata Y.
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Journal Title
PLoS One
Volume: 15
Issue: 4
Pages: 0231265-0231265
DOI
Related Report
Peer Reviewed / Open Access
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