Function and regulation of F‑box/WD repeat‑containing protein 7 (Review)

Abstract

The ubiquitin-proteasome system is an important post-translational modification system involved in numerous biological processes, such as cell cycle regulation, gene transcription, signal transduction, apoptosis, differentiation and development. F-box/WD repeat-containing protein 7 (FBXW7) is one of the most studied F-box (FBX) proteins, serving as substrate recognition component of S phase kinase-associated protein 1-Cullin 1-FBX protein complexes. As a tumor suppressor, FBXW7 recognizes numerous proto-oncoproteins and promotes their ubiquitination and subsequent proteasomal degradation. FBXW7 is regulated at different levels, leading to tunable and specific control of the activity and abundance of its substrates. Therefore, genetic mutations or decreases in its expression serve an important biological role in tumor development. In-depth studies and identification of additional substrates targeted by FBXW7 have suggested a signaling network regulated by FBXW7, including its tumor-inhibitory role. The present review focused on the role of FBXW7 in tumor suppression and its application in cancer therapy. Contents 1. Introduction 2. Transcriptional and translational regulation of FBXW7 expression 3. Post-translational modifications of FBXW7 4. Genetic alterations of FBXW7 in cancers 5. Substrates and mechanisms of FBXW7 involved in tumor suppression 6. Therapeutic exploitation of FBXW7 signaling 7. Conclusions

FBXW24 controls female meiotic prophase progression by regulating SYCP3 ubiquitination

“…Although not direct evidence, the mutations of diverse arginine residues in human FBXW7 caused an overactivation of multiple kinases involved in cell proliferation, transformation, and metastasis, and arginine and lysine are residues that can undergo diverse post‐translational modifications 29 . FBXW7 is a well‐known E3 ubiquitin ligase regulating various important proteins 30,31 . Furthermore, I‐Tasser showed that the R‐rich C‐terminal region of FBXW24 (Figure 6E) is structurally similar to the R‐rich C‐terminal region of FBXW7 (Figure 6D), which belongs to the WD40 repeat motif (Figure 6C–E and Movie S5).…”

“…29 FBXW7 is a well-known E3 ubiquitin ligase regulating various important proteins. 30,31 Furthermore, I-Tasser showed that the R-rich C-terminal region of FBXW24 (Figure 6E) is structurally similar to the R-rich C-terminal region of FBXW7 (Figure 6D), which belongs to the WD40 repeat motif (Figure 6C-E and Movie S5). Generally, a group of several adjacent charged residues might be the key sites for enzymatic activity.…”

FBXO17 Inhibits the Wnt/β-Catenin Pathway and Proliferation of Ishikawa Cells

“…Decreased FBXO17 was observed at both the mRNA and protein levels in UCEC tissues and was confirmed to be associated with histological grade. According to previous studies, the dysregulation of F-box proteins in tumors may be ascribed to several causes, such as aberrant DNA methylation [32,33], translational regulation by noncoding RNAs [34], gene mutation or CCAAT/enhancer-binding protein δ (CEBPδ) regulation under hypoxic conditions [35], but the regulation of FBXO17 in UCEC has not been previously shown, to the best of our knowledge.…”

The Role of FBXW7 in Gynecologic Malignancies

“…Post-translational modifications of FBXW7 involve its phosphorylation, autoubiquitination, deubiquitination, dimerization, and localization [44].…”