2006 Fiscal Year Final Research Report Summary
Analysis of the mechanisms of the proteolysis of p27 in Ewing's sarcoma and its clinical application.
| Project/Area Number |
17591580
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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 |
Orthopaedic surgery
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
TANAKA Kazuhiro Kyushu University, Hospital, Research Associate, 大学病院, 助手 (10274458)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Ewing's Sarcoma / EWS-Flil / fusion gene / p27 / ubiquitin-proteasome / senescence |
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| Research Abstract |
The translocation t(11;22)(q24:q12) is a specific chromosomal abnormality detected in Ewing's sarcoma (ES). The translocation results in an EWS-Fli1 fusion gene. Recent studies have evaluated transforming potentials of the fusion gene products acting as an aberrant transcription factor. However, the biological significance of EWS-Fli1 is still unknown. We have found that there is a correlation between the expression levels of the EWS-Fli1 fusion gene and the proliferative activities of ES cells, and that EWS-Fli1 inhibited the expression of p21 and p27 whereas induced the expression of cyclin E and D1. Among these target factors involved in the G1/S transition in the cell cycle, p27 showed the strongest correlation with the prognosis of the patients with ES. In the present study, we aimed to investigate the mechanisms by which EWS-Fli1 inhibits the expression of p27 in ES. When the expression of EWS-Fli1 was inhibited by siRNA, the expression of a p27-specific ubiquitin-ligase, Skp2, was also inhibited. The expression level of Skp2 was paralleled with that of EWS-Fli1 in ES cells. EWS-Fli1 enhanced the ubiquitination of p27 protein. The challenge of proteasome inhibitor to ES cells significantly increased the expression of p27 and inhibited the growth of ES cells both in vitro and in vivo. On the other hand, the proteasome inhibitor could not inhibit the growth of the drug-resistant ES cells. The co-treatment with the efflux pump inhibitor and the proteasome inhibitor efficiently inhibited the growth of the drug-resistant ES cells. These results suggest that the EWS-Fli1 might increase the expression of Skp2 resulting in the ubiquitination and degradation of p27 protein in ES cells. The proteasome inhibitor might be a promising reagent for novel molecular targeted therapy for ES.
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[Journal Article] Involvement of p-glycoprotein and MRP1 in resistance to the cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells.2006
Author(s)
Okada T, Tanaka K, Nakatani F, Sakimura R, Matsunobu T, Li X, Hanada M, Nakamura T, Oda Y, Tsuneyoshi M, Iwamoto Y
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Journal Title
Int.J.Cancer 118
Pages: 90-97
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The possible role of EWS-Fli1 in evasion of senescence in Ewing's family tumors.2006
Author(s)
Matsunobu T, Tanaka K, Nakamura T, Nakatani F, Sakimura R, Hanada M, Li X, Okada T, Oda Y, Tsuneyoshi M, Iwamoto Y
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Journal Title
Cancer Res. 66
Pages: 803-811
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Chromosomal and microsatellite instability of malignant peripheral nerve sheath tumors : The study of 10 tumors from 9 patients.2006
Author(s)
Kobayashi C, Oda Y, Takahira T, Izumi T, Kawaguchi K, Yamamoto H, Tamiya S, Oda S, Tanaka K, Matsuda S, Iwamoto Y, Tsuneyoshi M
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Journal Title
Cancer Genet.Cytogen. 165
Pages: 98-105
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Frequent alteration of p16INK4a/p14ARF and p53 pathways of round cell appearance in myxoid/round cell liposarcoma : Altered p53 gene and reduced p14ARF expression correlates with poor prognosis.2005
Author(s)
Oda Y, Yamamoto H, Takahira T, Kobayashi C, Kawaguchi K, Tateishi N, Nozuka Y, Tamiya S, Tanaka K, Matsuda S, Yokoyama R, Iwamoto Y, Tsuneyoshi M
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Journal Title
J.Pathol. 207
Pages: 410-421
Description
「研究成果報告書概要(欧文)」より
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