| Project/Area Number |
13670226
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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 |
Experimental pathology
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| Research Institution | Keio University |
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Principal Investigator |
FUKUMA Mariko Keio University, School of Medicine Instructor, 医学部, 助手 (60101995)
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| Co-Investigator(Kenkyū-buntansha) |
UMEZAWA Akihiro National Research Institute for Child Health and Developme Director of Department, 生殖医療研究部, 部長(研究職) (70213486)
HATA Jun-ichi National Research Institute for Child Health and Development General Director, 所長(研究職) (90051614)
OKITA Hajime Department of Reproductive Biology Keio University, School of Medicine Instructor, 医学部, 助手 (50317260)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Ewing sarcoma / chimeric protein / EWS / ets / bHLH transcription factor / suppression of differentiation / Id2 / ld2 / ユーイング肉腫 |
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| Research Abstract |
Ewing sarcoma is one of the common solid tumors of bone and soft tissue in childhood and adolescents. The chromosomal translocation specifically linked to this tumor results in the generation of fusion proteins (EWS/ets) comprising the amino terminal portion of EWS and the DNA binding domain of ets transcription factors. The target genes of EWS/ets oncoproteins have been investigated to understand the oncogenic mechanism in Ewing sarcoma. Because the ets proteins augment expression of transcription factors in various lineages of differentiation, we presumed that there would be genes whose ectopic expressions induced by chimeric proteins are responsible for the undifferentiated phenotype, and high malignant potential of this tumor. We sought genes specifically expressed in Ewing sarcoma and found enhanced expression of the Id genes. Id proteins function in a dominant negative manner by sequestering ubiquitously expressed or cell-type restricted basic helix-loop-helix (bHLH) transcription factors, thereby blocking the binding of bHLH proteins to DNA. High levels of Id2 transcripts were detected in Ewing sarcoma cell lines and tumor tissues, and the levels were reduced by the treatment of cells with differentiation inducing agents. The EWS/ets chimeric proteins activated the Id2 gene via the 5'-upstream promoter sequence. The chimeric proteins worked more effectively than corresponding ets proteins. Chromatin-immunoprecipitation revealed a direct interaction of EWS/Fli-1 with the promoter regions of the Id2, cyclin D1, and c-myc genes. Since EWS/Fli-1 transactivates c-myc, a cooperative action of the chimeric protein and c-myc leads to overexpression of Id2. In the present study, we suggest that Id2 is a target of the chimeric proteins and that the c-myc/Id2 pathway plays a pivotal role in the oncogenic processes provoked by EWS/ets proteins.
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