1999 Fiscal Year Final Research Report Summary
Analysis of molecular mechanisms of leukemia development
| Project/Area Number |
09307021
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | The University of Tokyo |
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Principal Investigator |
HIRAI Hisamaru Internal Medicine, University of Tokyo Hospital, Associate Professor, 医学部・附属病院, 助教授 (90181130)
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| Co-Investigator(Kenkyū-buntansha) |
HONDA Hiroaki Internal Medicine, University of Tokyo Hospital, Assistant Professor, 医学部・附属病院, 助手 (40245064)
CHIBA Shigeru Internal Medicine, University of Tokyo Hospital, Assistant Professor, 医学部・附属病院, 助手 (60212049)
MITANI Kinuko Internal Medicine, University of Tokyo Hospital, Assistant Professor, 医学部・附属病院, 助手 (50251244)
OGAWA Seishi Internal Medicine, University of Tokyo Hospital, Assistant Professor, 医学部・附属病院, 助手 (60292900)
SASAKI Ko Internal Medicine, University of Tokyo Hospital, Assistant Professor, 医学部・附属病院, 助手 (60282638)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Leukemia / Evi-1 / TGFβ / Smad3 / Cell growth / JNK / Stress / Apoptosis |
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| Research Abstract |
Evi-1 encodes a zinc finger protein implicated in leukemic transform ation of hematopoietic cells. Evi-1 posses seven and three repeats of zinc finger motifs separated into two domains, and characteristics as a transcriptional regulator have been described. Although Evi-1 is thought to possess the abilities to promote growth or to block differentiation in some types of cell, its biological functions have been poorly understood. To explore mechanisms that underlie oncogenesis induced by Evi-1, we investigated whether Evi-1 perturbs signalling of transforming growth factor β (TGFβ), one of the most studied growth regulatory factors that inhibit proliferatic of a wide range of cell types. We demonstrated that Evi-1 represses TGFβ signalling and antagonizes growth-inhibitory effects of TGFβ. Two separate regions of Evi-1 are responsible for this repression, one of which is tl first zinc finger domain. Through this domain, Evi-1 physically interacts with Smad3, an intracellular mediato TGFβ signalling, thereby suppressing the transcriptional activity of Smad3. These results define a novel functi of Evi-1 as a repressor of signalling components of TGFβ. We also showed that Evi-1 acts as an inhibitor of c Jun N-terminal kinase (JNK), also called stress-activated protein kinase (SAPK), a class of mitogen-activated protein (MAP) kinasess which is implicated in apoptosis, the immuneresponse and signalling pathway of hematopoietic cytokines. Evi-1 physically interacts with JNK/SAPK and protects cells from ultraviolet (UV)- induced cell death. This reveals a novel biochemical and biological activity of Evi-1, which provides an evider for inhibition of JNK/SAPK by a nuclear oncogene product. Among MAP kinases, Evi-1 selectively inhibits JNK/SAPK and thus blocks apoptotic cell death induced by cellular stresses, thereby contributing to oncogenic transformation of cells.
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