Year: 2013
Type: review
Abstract: 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.
Source: Current Pharmaceutical Design
Authors: Yongchao Zhao, Yi Sun
Institution: University of Michigan
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funder: National Cancer Institute
Awards: Anti-pancreatic tumorigenesis by inactivation of SAG/RBX2 E3 ubiquitin ligase, The role of FBXW2 as a novel lung tumor suppressor that cross-talks with oncogenic beta-TrCP and SKP2, SAG E3 ubiquitin ligase in regulation of transformation and carcinogenesis, Role of SAG/RBX2 E3 Ubiquitin Ligase in Skin Carcinogenesis
OpenAlex ID: W1985593766