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dc.contributor.author | Doi, Keiko | en |
dc.contributor.author | Imai, Takahiko | en |
dc.contributor.author | Kressler, Christopher | en |
dc.contributor.author | Yagita, Hideo | en |
dc.contributor.author | Agata, Yasutoshi | en |
dc.contributor.author | Vooijs, Marc | en |
dc.contributor.author | Hamazaki, Yoko | en |
dc.contributor.author | Inoue, Joe | en |
dc.contributor.author | Minato, Nagahiro | en |
dc.contributor.alternative | 圡井, 恵子 | ja |
dc.contributor.alternative | 井上, 浄 | ja |
dc.contributor.alternative | 湊, 長博 | ja |
dc.date.accessioned | 2015-03-11T04:50:07Z | - |
dc.date.available | 2015-03-11T04:50:07Z | - |
dc.date.issued | 2015-01-23 | - |
dc.identifier.issn | 2045-2322 | - |
dc.identifier.uri | http://hdl.handle.net/2433/196068 | - |
dc.description.abstract | The Rap G protein signal regulates Notch activation in early thymic progenitor cells, and deregulated Rap activation (Rap(high)) results in the development of Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL). We demonstrate that the Rap signal is required for the proliferation and leukemogenesis of established Notch-dependent T-ALL cell lines. Attenuation of the Rap signal by the expression of a dominant-negative Rap1A17 or Rap1GAP, Sipa1, in a T-ALL cell line resulted in the reduced Notch processing at site 2 due to impaired maturation of Adam10. Inhibition of the Rap1 prenylation with a geranylgeranyl transferase inhibitor abrogated its membrane-anchoring to Golgi-network and caused reduced proprotein convertase activity required for Adam10 maturation. Exogenous expression of a mature form of Adam10 overcame the Sipa1-induced inhibition of T-ALL cell proliferation. T-ALL cell lines expressed Notch ligands in a Notch-signal dependent manner, which contributed to the cell-autonomous Notch activation. Although the initial thymic blast cells barely expressed Notch ligands during the T-ALL development from Rap(high) hematopoietic progenitors in vivo, the ligands were clearly expressed in the T-ALL cells invading extrathymic vital organs. These results reveal a crucial role of the Rap signal in the Notch-dependent T-ALL development and the progression. | en |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Nature Publishing Group | en |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ | en |
dc.subject | Acute lymphocytic leukaemia | en |
dc.subject | Leukaemia | en |
dc.title | Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia. | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Scientific reports | en |
dc.identifier.volume | 5 | - |
dc.relation.doi | 10.1038/srep07978 | - |
dc.textversion | publisher | - |
dc.identifier.artnum | 7978 | - |
dc.identifier.pmid | 25613394 | - |
dcterms.accessRights | open access | - |
出現コレクション: | 学術雑誌掲載論文等 |
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