| Project/Area Number |
08671214
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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 | TOKYO UNIVERSITY |
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Principal Investigator |
TANAKA Tomotuki TOKYO UNIVERSITY,Associate Professor, 医学部・附属病院, 助手 (50227154)
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| Co-Investigator(Kenkyū-buntansha) |
KUROKAWA Mineo TOKYO UNIVERSITY,Research Associate, 医学部・附属病院, 医員
SASAKI Ko TOKYO UNIVERSITY,Associate Professor, 医学部・附属病院, 助手 (60282638)
HIRAI Hisamaru TOKYO UNIVERSITY,Assistant Professor, 医学部・附属病院, 助教授 (90181130)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1997: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1996: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | AML1 gene / Transcription Factor / Hematopoietic Cell / Cell Diffrerntiation / Cell Proliferation / Leukemia / Phosphorylation |
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| Research Abstract |
The AML1 gene on chromosomal 21 is disrupted in the(8 ; 21) (q22 ; q22)and (3 ; 21) (q26 ; q22)translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by alternative splicing. Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transactivation domain. We demonstrate that(1)AML1a totally supress granulocytic differentiation and stimulates cell proliferation in 32Dc13 murine myeloid cells treated with granulocyte colonystimulating factor. These effect of AML1a were canceled by the concominant over expression of AML1b.(2)AML1b enhance transactivation level through PEBP2 sites. AML1a, which on its own has no effect as a transcriptional regulator, dominantly supress transcriptional activation by AML1b. (3)AML1a exhibits the higher affinity for PEBP2 sites copmpared with AML1b. And we also demonstrate that AML1 is phosphorylated in vivo on two serine residues within the proline-, serine-, and threonine-rich resion, with dependence on the activation of extracellular signal-regulated kinase (ERK). The major residue of phosphorylation is S249 in PST domain, and the additional residue is S266. ERK-dependent phosphorylation of AML1 does not affect its DNA-binding affinity but potenciates the transactivation ability of AML1. And this phosphorylation is essential for anchorage independent growth of NIH3t3 cells. Furthermore, we prove that AML1 associate with ERK consitiutively, and that this association does not affect to kinase activity of ERK nor phosphorylation of AML1. It is also revealed that AML1 function in under redox regulations.
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