F-Box Proteins and Cancer.

Kanae Yumimoto,Yuhei Yamauchi,Keiichi I Nakayama

doi:10.3390/cancers12051249

Abstract

Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

Highlights

Ubiquitylation-dependent proteasomal degradation of target proteins is an irreversible reaction that contributes to the regulation of many eukaryotic cellular processes—such as cell division, growth, and differentiation—at the level of selective protein turnover [1]
F-box proteins are responsible for substrate recognition by each SKP1–CUL1–F-box protein (SCF) complex, and they harbor two key functional domains: The F-box domain, which mediates association with the other components of the complex via direct interaction with S-phase kinase-associated protein 1 (SKP1), and the COOH-terminal domain, which interacts with substrates [4]
Mice deficient in SKP2 are viable, cells of the mutant animals contain markedly enlarged nuclei with polyploidy and multiple centrosomes as well as manifest a reduced growth rate and increased level of apoptosis [21]. These phenotypes are reversed by additional ablation of p27KIP1, suggesting that this cyclin-dependent kinases (CDKs) inhibitor is the major substrate targeted by SCFSKP2 [22]

Summary

Introduction

Ubiquitylation-dependent proteasomal degradation of target proteins is an irreversible reaction that contributes to the regulation of many eukaryotic cellular processes—such as cell division, growth, and differentiation—at the level of selective protein turnover [1]. F-box proteins are responsible for substrate recognition by each SCF complex, and they harbor two key functional domains: The F-box domain, which mediates association with the other components of the complex via direct interaction with SKP1, and the COOH-terminal domain, which interacts with substrates [4]. The SCF complex functions together with E1 and to mediate the to ubiquitylation of target proteins. Each F-box binds to SKP1 its and to a substrate via its COOH-terminal substrate interaction domain, thereby presenting the target. F-box domain and to a substrate via its COOH-terminal substrate interaction domain, thereby protein for ubiquitylation. The SCFfor complex-mediated a polyubiquitin chain on a substrate presenting the target protein ubiquitylation. We highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box as well as discuss how such F-box proteins are deployed to regulate such substrates in a manner dependent on the localization or function of the latter

Representative F-Box Proteins Related to Cancer

Distribution

Tumor Promoters Regulated by Multiple F-Box Proteins

Cyclin D1

Tumor Suppressors Regulated by F-Box Proteins

Conclusions