Molecular Mechanism of CRBN in the Activity of Lenalidomid eagainst Myeloma--Review.
10.7534/j.issn.1009-2137.2018.04.050
- Author:
Wen-Jing FAN
1
,
2
;
Zhi-Qiao FAN
3
;
Mei-Juan YANG
4
;
Yao-Zhu PAN
2
;
Hai BAI
5
Author Information
1. The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, Gansu Province, China
2. The Center of Hematologic Diseases of Chinese PLA, Lanzhou Military Command General Hospital, Lanzhou 730050, Gansu Province, China.
3. Gansu Unversity of Traditional Chinese Medicine,Lanzhou 730000, Gansu Province, China.
4. The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, Gansu Province, China.
5. Gansu Unversity of Traditional Chinese Medicine,Lanzhou 730000, Gansu Province, China E-mail: baihai98@tom.com.
- Publication Type:Journal Article
- MeSH:
Cullin Proteins;
Humans;
Hydrogen Peroxide;
Multiple Myeloma;
Peptide Hydrolases;
Proteolysis;
Thalidomide;
Ubiquitination
- From:
Journal of Experimental Hematology
2018;26(4):1240-1243
- CountryChina
- Language:Chinese
-
Abstract:
Cereblon（CRBN) is a brain-associated protein with ionic protease activity, which interacts with DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and regulator of Cullins 1 (RoC1) to form the functional E3 ubiquitin ligase complex(CRBN-CRL4) that performs proteolysis via the ubiquitin-proteasome pathway. And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex, leading to increased ubiquitination and proteasome-dependent degradation, thus resulting in anti-myeloma activity. The substrates binding to this complex are IKZF1, IKZF3 proteins and GS, etc. The CRBN-dependent degradation of IKZF1 and IKZF3 after lenalidomide treatment is also the result of HO-mediated oxidative stress. In addition to ubiquitination, lenalidomide also mediates ubiquitin-independent pathways that prevent CRBN from binding to CD147-MCT1 in a competitive manner to regulate its antitumor activity. Lenalidomide can also play a role in multiple myeloma(MM) cells by modulating miRNA levels and CRBN binding to downstream protein AGO2 expression. Thus, there are many molecular mechanisms of lenalidomide anti-myeloma activity. This review summarizes the molecular mechanisms of CRBN in lenalidomide against myeloma activity in terms of ubiquitin-dependent and ubiquitin-independent pathways.
