Molecular Mechanism of CRBN in the Activity of Lenalidomid eagainst Myeloma--Review / 中国实验血液学杂志
Journal of Experimental Hematology
;
(6): 1240-1243, 2018.
Article
in Chinese
| WPRIM
| ID: wpr-689498
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Peptide Hydrolases
/
Thalidomide
/
Cullin Proteins
/
Ubiquitination
/
Proteolysis
/
Hydrogen Peroxide
/
Multiple Myeloma
Limits:
Humans
Language:
Chinese
Journal:
Journal of Experimental Hematology
Year:
2018
Type:
Article
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