| RRC ID |
65687
|
| Author |
Doi K, Imai T, Kressler C, Yagita H, Agata Y, Vooijs M, Hamazaki Y, Inoue J, Minato N.
|
| Title |
Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia.
|
| Journal |
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.
|
| Volume |
5
|
| Pages |
7978
|
| Published |
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
|
| Resource |
| Human and Animal Cells |
TALL-1(RCB2084) |
