Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies

Abstract

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

Fig 1.

Protein ubiquitination and subsequent degradation is dependent on several integrated enzymatic cascades. The formation of the polyubiquitin chain is catalyzed by a cascade of enzymes. The E1 enzyme (ubiquitin-activating enzyme [UAE]) activates ubiquitin (Ub) and then transfers it to one of dozens of E2 enzymes (ubiquitin-carrier protein [UCP]). The E2-Ub complex then interacts with a specific E3 enzyme to catalyze the covalent formation of a polyubiquitin chain on a substrate protein specifically recruited by that E3. E3 ubiquitin ligases can be divided into three classes: HECT (homologous to E6-AP carboxy terminus), U-box, and RING (really interesting new gene). Within the RING family, there are two additional subclasses: cullin-containing RING-finger ligases (CRLs) and other RINGs. CRLs represent a unique subclass in that they must undergo neddylation to become activated and participate in the ubiquitin proteasome system (UPS). Neddylation is an enzymatic cascade homologous to ubiquitination involving E1 (NEDD8-activating enzyme [NAE]) and E2 (Ubc12) enzymes. Deubiquitinases (DUBs) function to deubiquitinate proteins, thus altering their fate within the UPS. Novel targeted inhibitors of enzymes within the UPS, including UAE, NAE, E3, DUBs, and proteasome inhibitors, are in preclinical and clinical development. UPL, ubiquitin-protein ligase.