Document Detail


Cullin-RING Ligases as attractive anti-cancer targets.
MedLine Citation:
PMID:  23151137     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ubiquitin-proteasome system (UPS) promotes the timely degradation of short-lived proteins with key regulatory roles in a vast array of biological processes, such as cell cycle progression, oncogenesis and genome integrity. Thus, abnormal regulation of UPS disrupts the protein homeostasis and causes many human diseases, particularly cancer. Indeed, the FDA approval of bortezomib, the first class of general proteasome inhibitor, for the treatment of multiple myeloma, demonstrated that the UPS can be an attractive anti-cancer target. However, normal cell toxicity associated with bortezomib, resulting from global inhibition of protein degradation, promotes the focus of drug discovery efforts on targeting enzymes upstream of the proteasome for better specificity. E3 ubiquitin ligases, particularly those known to be activated in human cancer, become an attractive choice. Cullin-RING Ligases (CRLs) with multiple components are the largest family of E3 ubiquitin ligases and are responsible for ubiquitination of ~20% of cellular proteins degraded through UPS. Activity of CRLs is dynamically regulated and requires the RING component and cullin neddylation. In this review, we will introduce the UPS and CRL E3s and discuss the biological processes regulated by each of eight CRLs through substrate degradation. We will further discuss how cullin neddylation controls CRL activity, and how CRLs are being validated as the attractive cancer targets by abrogating the RING component through genetic means and by inhibiting cullin neddylation via MLN4924, a small molecule indirect inhibitor of CRLs, currently in several Phase I clinical trials. Finally, we will discuss current efforts and future perspectives on the development of additional inhibitors of CRLs by targeting E2 and/or E3 of cullin neddylation and CRL-mediated ubiquitination as potential anti-cancer agents.
Authors:
Yongchao Zhao; Yi Sun
Related Documents :
22666217 - Emerging targeted therapies for castration-resistant prostate cancer.
11035657 - Human herpesvirus 8 is not associated with sarcoidosis in japanese patients.
23061727 - Impact of cellular senescence in aging and cancer.
22565597 - Building cancer nursing skills in a resource-constrained government hospital.
17607917 - Clinical, biological, and molecular aspects of metastasis in colorectal cancer.
21042017 - Profile and frequency of p53 gene alterations in gastritis lesions from iran.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Current pharmaceutical design     Volume:  19     ISSN:  1873-4286     ISO Abbreviation:  Curr. Pharm. Des.     Publication Date:  2013  
Date Detail:
Created Date:  2013-04-25     Completed Date:  2013-10-28     Revised Date:  2014-05-29    
Medline Journal Info:
Nlm Unique ID:  9602487     Medline TA:  Curr Pharm Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  3215-25     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Boronic Acids / pharmacology
Cullin Proteins / metabolism
Drug Design
Humans
Molecular Targeted Therapy
Neoplasms / drug therapy*,  pathology
Proteasome Inhibitors / pharmacology
Pyrazines / pharmacology
Ubiquitin-Protein Ligases / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
CA118762/CA/NCI NIH HHS; CA156744/CA/NCI NIH HHS; CA170995/CA/NCI NIH HHS; CA171277/CA/NCI NIH HHS; R01 CA118762/CA/NCI NIH HHS; R01 CA156744/CA/NCI NIH HHS; R01 CA171277/CA/NCI NIH HHS; R21 CA170995/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Boronic Acids; 0/Cullin Proteins; 0/Proteasome Inhibitors; 0/Pyrazines; 0/bortezomib; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Regulation of Skeletal Muscle Plasticity by Glycogen Synthase Kinase-3?: A Potential Target for the ...
Next Document:  The Ubiquitin Proteasome System as a Potential Target for the Treatment of Neurodegenerative Disease...