2006 Fiscal Year Final Research Report Summary
Comprehensive Analyses of Intracellular Signaling Mechanism Underlying Thrombopoietin-independent Megakaryopoiesis
| Project/Area Number |
16590922
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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 |
Hematology
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| Research Institution | University of Tsukuba |
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Principal Investigator |
KOJIMA Hiroshi University of Tsukuba, Graduate School of Comprehensive Human Sciences, Associated Professor, 大学院人間総合科学研究科, 助教授 (10225435)
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| Project Period (FY) |
2004 – 2006
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| Keywords | megakaryocytes / thrombopoietin / platelet production / Bcl-xL / caspase-3 / p38MAPK / CD226 |
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| Research Abstract |
While differentiation of megakaryocytes (Mgk) from bone marrow stem cells is mediated by a lineage-specific cytokine, thrombopoietin (TPO), mature Mgk produce platelets independent of the effect of TPO. It has not been well elucidated about intracellular signaling mechanism and intercellular interaction that regulate platelet production from Mgk. Based on our previous observations, we in this study focused on caspase-3, p38MAPK, and CD226(DNAM-1).
By using Bim-/- and vav-Bcl-2 TG mice whose Mgk are resistant to caspase-3 activation, we analyzed the involvement of caspase activation in platelet. As Mgk obtained from these mice produced platelets normally both in vitro and in vivo experiments, we concluded that caspase-3 activation is not involved in platelet production from Mgk. In accordance with this observation, continuous expression of Bcl-xL protein was observed during megakaryopoiesis. We also clarified how the protein level of Bcl-xL is post-transcriptionally regulated (J Thromb Haemost 5 : 1274, 2007). By analyzing the phenotype of Bim-/- mice, we demonstrated that a BH3-only proapoptotic protein Bim, as well as an antiapoptotic protein Bcl-xL, regulates apoptosis of hematopoietic stem cells and early Mgk (in preparing for publication).
As regards the role of CD226, an adhesion molecule belonging to immunoglobulin superfamily, we found that CD226 is expressed only in mature Mgk. By experiments using a function-blocking antibody, we proved that interaction of Mgk with stromal cells inhibits platelet production through the signal from CD226. We are currently under investigation by using CD226-/-mice.
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