2019 Fiscal Year Final Research Report
Elucidation of the molecular basis of IMiDs' action
Project/Area Number |
17H04213
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Hematology
|
Research Institution | Tokyo Medical University |
Principal Investigator |
Ito Takumi 東京医科大学, 医学部, 准教授 (30533179)
|
Project Period (FY) |
2017-04-01 – 2020-03-31
|
Keywords | サリドマイド / セレブロン / ユビキチン / PROTACs / CRBN |
Outline of Final Research Achievements |
In this study, I aimed to elucidate the mechanistic basis of the CRBN-based IMiDs signaling. I have analyzed a substrate candidate S1 and a non-substrate X1 of CRBN, a substrate receptor of CRL4 E3 ubiquitin ligase. I found S1 is an exact IMiD-dependent CRBN substrate and is responsible for anti-DLBCL (Diffused Large B-Cell Lymphoma) and anti-angiogenesis other than anti-myeloma effects of IMiDs. I also found the structural degron of S1. I determined the CRBN-binding domain in X1. I newly isolated and analyzed several new CRBN neosubstrates.
|
Free Research Field |
ケミカルバイオロジー・分子生物学
|
Academic Significance and Societal Importance of the Research Achievements |
免疫調節薬(IMiDs)は現在、多発性骨髄腫などの優れた治療薬として世界的にも脚光を浴びているが、その分子基盤について不明な点が多かった。今回、研究代表者によりIMiDsの標的であるCRBNのさらに下流に位置するS1および他の基質の実態が明らかになった。S1はびまん性大細胞型B細胞リンパ腫や血管新生などにも関わることが判明し、IMiDsのさらなる適応拡大に貢献できる成果をあげられたといえる。
|