Analysis of thalidomide induced CRBN-E3-ubiquitin-ligase inhibition mechanism
| Project/Area Number |
23710267
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Chemical biology
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| Research Institution | Tokyo Medical University (2013)
Tokyo Institute of Technology (2011-2012) |
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Principal Investigator |
ITO Takumi 東京医科大学, 医学部, 講師 (30533179)
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| Project Period (FY) |
2011 – 2013
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | サリドマイド / セレブロン / ユビキチン / 催奇性 / 多発性骨髄腫 / IMiDs / E3 / ポマリドマイド / レナリドマイド / ケミカルバイオロジー / ユビキチンリガーゼ |
|---|
| Research Abstract |
Thalidomide is known for its teratogenicity, however it is also recognised as a clinically effective drug for the treatment of myeloma. Although the molecular targets of thalidomide were a long-standing question, we recently identified protein cereblon (CRBN) as a primary target of thalidomide induced teratogenicity. Our data suggest that thalidomide inhibits the E3 ubiquitin ligase function of CRBN but the detail mechanism is still largely unknown. In this study, I have analysed the inhibitory mechanism of the CRBN function by thalidomide using biochemical approaches. My data suggest that thalidomide binding to CRBN alters CRBN-E3-ubiquitin-ligase substrate specificity. Thus, thalidomide-bound CRBN may no longer recognise original substrates resulting in the inhibition of its E3-ubiquitin-ligase function.
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN)2014
Author(s)
A. K. Gandhi, J. Kang, C. G. Havens, T. Conklin, Y. Ning, L. Wu, T. Ito, H. Ando, M. F. Waldman, A. Thakurta, A. Klippel, H. Handa, T.O. Daniel, P. H. Schafer, R. Chopra
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Journal Title
Br. J. Haematol.
Volume: 164
Issue: 6
Pages: 811-821
DOI
Related Report
Peer Reviewed
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[Journal Article] Vesnarinone Suppresses TNF α mRNA Expression by Inhibiting Valosin-containing Protein2013
Author(s)
Hotta K, Nashimoto A, Yasumura E, Suzuki M, Azuma M, Iizumi Y, Shima D, Nabeshima R, Hiramoto M, Okada A, Sakata-Sogawa K, Tokunaga M, Ito T, Ando H, Sakamoto S, Kabe Y, Aizawa S, Imai T, Yamaguchi Y, Watanabe H, Handa H
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Journal Title
Mol Pharmacol
Volume: Vol.83
Issue: 5
Pages: 930-938
DOI
Related Report
Peer Reviewed
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[Journal Article] Identification of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel target of Bisphenol A.2012
Author(s)
Ito, Y., Ito, T., Karasawa, S., Enomoto, T., Nashimoto, A., Hase, Y., Sakamoto, S., Ito, T., Mimori, T., Matsumoto, Y., Yamaguchi, Y., Handa, H.
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Journal Title
PLos ONE
Volume: 7(12)
Issue: 12
Pages: e50481-e50481
DOI
Related Report
Peer Reviewed
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