| Project/Area Number |
21790333
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Japanese Foundation For Cancer Research |
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Principal Investigator |
YOKOYAMA Takashi Japanese Foundation For Cancer Research, 癌研究所発がん研究部, 研究員 (00535833)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | Trib1 / 白血病 / MAPK / DS-AMKL / MAPキナーゼ経路 / C/EBPα / C / EBPα |
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| Research Abstract |
Our previous study indicated that Trib1 is a leukemia disease gene as well as a collaborator of Hoxa9/Meis1 in myeloid leukemogenesis. We have identified that Trib1 interaction with MEK1 and subsequent enhanced MAPK activity that are mediated with the MEK1 binding motif, ILLHPWF, are key molecular mechanisms for leukemogenesis. In addition, we have clarified that activation of the MAP kinase pathway by Trib1 is also required for degradation of C/EBPα. These studies uncover the role of Trib1 as an important adaptor that connects the RAS-MAPK pathway with C/EBP transcription factors as well as its importance in hematological malignancies. Moreover, we have identified a somatic point mutation of TRIB1 in a human case of Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL). The point mutation results in amino acid conversion arginine 107 to leucine in the pseudokinase domain. The TRIB1 R107L mutation remained in leukocytes of the remission stage when the GATA1 mutation disappeared, indicating that the TRIB1 mutation is a very early genetic event. Introduction of the Trib1 R107L mutant into murine bone marrow cells induced AML with shorter latency than that of wild type. Further, the enhancing effects of Trib1 on phosphorylation of ERK1/2 and degradation of C/EBPα were more remarkable by R107L expression. These results suggest that TRIB1 R107L is a gain-of-function mutation in a DS-AMKL case.
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