論文 - 詳細
| RRC ID | 65687 |
|---|---|
| 著者 | Doi K, Imai T, Kressler C, Yagita H, Agata Y, Vooijs M, Hamazaki Y, Inoue J, Minato N. |
| タイトル | Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia. |
| ジャーナル | Sci Rep |
| 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. |
| 巻・号 | 5 |
| ページ | 7978 |
| 公開日 | 2015-1-23 |
| DOI | 10.1038/srep07978 |
| PII | srep07978 |
| PMID | 25613394 |
| PMC | PMC4303867 |
| MeSH | Animals Cell Line, Tumor Cell Proliferation* GTPase-Activating Proteins / genetics GTPase-Activating Proteins / metabolism* Mice Mice, Knockout Nuclear Proteins / genetics Nuclear Proteins / metabolism* Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism* Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction* rap1 GTP-Binding Proteins / genetics rap1 GTP-Binding Proteins / metabolism* |
| IF | 3.998 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | TALL-1(RCB2084) |