Abstract
The ubiquitin–proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to plays a critical role in human cancer. Activation of oncogenic factors and inhibition of tumor suppressors have been shown to be essential for cancer development, and protein ubiquitination has been linked to the regulation of oncogenic factors and tumor suppressors. Three kinases, AKT, extracellular signal-regulated kinase, and IκB kinase, we refer to as oncokinases, are activated in multiple human cancers. We and others have identified several key downstream targets that are commonly regulated by these oncokinases, some of which are regulated directly or indirectly via ubiquitin-mediated proteasome degradation, including FOXO3, β-catenin, myeloid cell leukemia-1, and Snail. In this review, we summarize these findings from our and other groups and discuss potential future studies and applications in the clinic.
Highlights
UBIQUITIN–PROTEASOME SYSTEM AND CANCER In order to maintain cellular homeostasis, the amount of proteins in cells is selectively controlled in protein synthesis and in protein degradation
The HECT domain-containing E3 ligase can receive ubiquitin from the E2 protein first through an active-site cysteine of its HECT domain interacts with its substrate to catalyze the conjugation of the activated ubiquitin to the substrate (Kee and Huibregtse, 2007)
Since the specificity of the target proteins for proteasome-mediated degradation is dependent on the interaction between the E3 ligases and their targets, the E3 ubiquitin ligases are critical for regulating the expression levels of key short-lived proteins
Summary
UBIQUITIN–PROTEASOME SYSTEM AND CANCER In order to maintain cellular homeostasis, the amount of proteins in cells is selectively controlled in protein synthesis and in protein degradation. The ubiquitin–proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to plays a critical role in human cancer. Since the specificity of the target proteins for proteasome-mediated degradation is dependent on the interaction between the E3 ligases and their targets, the E3 ubiquitin ligases are critical for regulating the expression levels of key short-lived proteins.
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