| Project/Area Number |
11470208
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Dokkyo University School of Medicine (2000-2001)
The University of Tokyo (1999) |
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Principal Investigator |
NAKAMURA Yuichi Dokkyo University School of Medicine, Department of Hermatology, Professor, 医学部, 教授 (50251244)
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| Co-Investigator(Kenkyū-buntansha) |
MAKI Kazuhiro Dokkyo University School of Medicine, Department of Hermatology, Assistant Professor, 医学部, 助手 (50337391)
WAGA Kazuo Dokkyo University School of Medicine, Department of Hermatology, Lecturer, 医学部, 講師 (00285917)
NAKAMURA Yuichi Dokkyo University School of Medicine, Department of Hermatology, Lecturer, 医学部, 講師 (20227896)
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| Project Period (FY) |
1999 – 2001
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| Keywords | AML1 / EVI-1 / TGFβ / CtBP / Smad3 / JNK / apoptosis / MLL / MEN / p53 |
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| Research Abstract |
AML1/EVI-1 is a chimeric transcription factor that plays a causative role in blastic transformation of chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS). AML1/EVI-1 repressed transcription through PAI-1 promoter that was activated by TGFβ signals. AML1/EVI-1 specifically bound to an intracellular signal transducer of TGFβ Smad-3, and inhibited its functions. Because AML1/EVI-1 bound to a corepressor CtBP, recruitment of histone deacetylase could be an underlying mechanism. AML1/EVI-1 blocked differentiation of 32D cells induced by G-CSF, depending on the CtBP-binding region in the EVI-1 portion. These data indicate that AML1/EVI-1 progresses CML or MDS to acute leukemia partly through abolishing TGFβ signals. On the other hand, EVI-1 bound to JNK through the 1st zinc finger domain and inhibited its kinase activities stimulated by several cellular stresses including UV. EVI-1 protected 3T cells from apoptosis depending on the 1st zinc finger domain. Therefore, blocking JNK-mediated apoptosis could be another mechanism in development of leukemia by AML1/EVI-1.
MLL/MEN (also termed as ELL) is a leukemia-related fusion protein found in acute myeloid leukemia or MDS-derived leukemia. Because MEN is an RNA polymerase factor, MLL/MEN is also a chimeric transcription factor. Both MEN and MLL/MEN bound to p53 and repressed its transcriptional abilities through the p53-binding sites. MEN was found to bind to p53 through the N-terminal portion and inhibit its transcription through the p53-binding sites. MEN stimulated growth of Rat1 cells in a semi-solid agar depending of p53-binding or repressing domain. Overexpression or aberrant expression of MEN may play an important role in development of myeloid leukemia. We generated knockout mice of MEN. They were embryonic lethal, and die before E6.5 and after implantation. MEN should play a non-redundant role as an elongation factor in postimplantation development of mice.
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