Roles of F-box proteins in cancer.
Wang Zhiwei,Liu Pengda,Inuzuka Hiroyuki,Wei Wenyi
Nature reviews. Cancer
F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.
10.1038/nrc3700
Ubiquitination-mediated degradation of cell cycle-related proteins by F-box proteins.
Zheng Nana,Wang Zhiwei,Wei Wenyi
The international journal of biochemistry & cell biology
F-box proteins, subunits of SKP1-cullin 1-F-box protein (SCF) type of E3 ubiquitin ligase complexes, have been validated to play a crucial role in governing various cellular processes such as cell cycle, cell proliferation, apoptosis, migration, invasion and metastasis. Recently, a wealth of evidence has emerged that F-box proteins is critically involved in tumorigenesis in part through governing the ubiquitination and subsequent degradation of cell cycle proteins, and dysregulation of this process leads to aberrant cell cycle progression and ultimately, tumorigenesis. Therefore, in this review, we describe the critical role of F-box proteins in the timely regulation of cell cycle. Moreover, we discuss how F-box proteins involve in tumorigenesis via targeting cell cycle-related proteins using biochemistry studies, engineered mouse models, and pathological gene alternations. We conclude that inhibitors of F-box proteins could have promising therapeutic potentials in part through controlling of aberrant cell cycle progression for cancer therapies.
10.1016/j.biocel.2016.02.005
The functions of F-box proteins in regulating the epithelial to mesenchymal transition.
Su Jingna,Yin Xuyuan,Zhou Xiuxia,Wei Wenyi,Wang Zhiwei
Current pharmaceutical design
Epithelial to mesenchymal transition (EMT) has been unraveled to regulate the tumor invasion and metastasis processes. In this review, in order to better understand the regulatory mechanisms of EMT, we describe that F-box proteins could be critically involved in regulating the EMT process in human cancers. Specifically, we discuss how these F-box proteins directly control the stability of EMT regulators such as E-cadherin, β-catenin, Twist, Slug, Snail and ZEB. Moreover, we summary mechanistically how the F-box proteins govern EMT progression through regulation of EMT inducers including Notch, NF-κB, Akt, Hedgehog, mTOR, and HIF-1α. Therefore, targeting these F-box proteins could be useful for treating human cancers.
F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects.
Tekcham Dinesh Singh,Chen Di,Liu Yu,Ling Ting,Zhang Yi,Chen Huan,Wang Wen,Otkur Wuxiyar,Qi Huan,Xia Tian,Liu Xiaolong,Piao Hai-Long,Liu Hongxu
Theranostics
E3 ubiquitin ligases play a critical role in cellular mechanisms and cancer progression. F-box protein is the core component of the SKP1-cullin 1-F-box (SCF)-type E3 ubiquitin ligase and directly binds to substrates by various specific domains. According to the specific domains, F-box proteins are further classified into three sub-families: 1) F-box with leucine rich amino acid repeats (FBXL); 2) F-box with WD 40 amino acid repeats (FBXW); 3) F-box only with uncharacterized domains (FBXO). Here, we summarize the substrates of F-box proteins, discuss the important molecular mechanism and emerging role of F-box proteins especially from the perspective of cancer development and progression. These findings will shed new light on malignant tumor progression mechanisms, and suggest the potential role of F-box proteins as cancer biomarkers and therapeutic targets for future cancer treatment.
10.7150/thno.42735
F-Box Proteins and Cancer.
Yumimoto Kanae,Yamauchi Yuhei,Nakayama Keiichi I
Cancers
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.
10.3390/cancers12051249
Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis.
Heo Jinho,Eki Rebeka,Abbas Tarek
Seminars in cancer biology
F-box proteins are substrate receptors of the SCF (SKP1-Cullin 1-F-box protein) E3 ubiquitin ligase that play important roles in a number of physiological processes and activities. Through their ability to assemble distinct E3 ubiquitin ligases and target key regulators of cellular activities for ubiquitylation and degradation, this versatile group of proteins is able to regulate the abundance of cellular proteins whose deregulated expression or activity contributes to disease. In this review, we describe the important roles of select F-box proteins in regulating cellular activities, the perturbation of which contributes to the initiation and progression of a number of human malignancies.
10.1016/j.semcancer.2015.09.015
F-box protein interactions with the hallmark pathways in cancer.
Randle Suzanne J,Laman Heike
Seminars in cancer biology
F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.
10.1016/j.semcancer.2015.09.013
Function and regulation of F-box/WD repeat-containing protein 7.
Zhang Zheng,Hu Qiangsheng,Xu Wenyan,Liu Wensheng,Liu Mengqi,Sun Qiqing,Ye Zeng,Fan Guixiong,Qin Yi,Xu Xiaowu,Yu Xianjun,Ji Shunrong
Oncology letters
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.
10.3892/ol.2020.11728
Involvement of F-BOX proteins in progression and development of human malignancies.
Uddin Shahab,Bhat Ajaz A,Krishnankutty Roopesh,Mir Fayaz,Kulinski Michal,Mohammad Ramzi M
Seminars in cancer biology
The Ubiquitin Proteasome System (UPS) is a core regulator with various protein components (ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, ubiquitin-protein E3 ligases, and the 26S proteasome) which work together in a coordinated fashion to ensure the appropriate and efficient proteolysis of target substrates. E3 ubiquitin ligases are essential components of the UPS machinery, working with E1 and E2 enzymes to bind substrates and assist the transport of ubiquitin molecules onto the target protein. As the UPS controls the degradation of several oncogenes and tumor suppressors, dysregulation of this pathway leads to several human malignancies. A major category of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four principal components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein (FBP). FBPs are the substrate recognition components of SCF complexes and function as adaptors that bring substrates into physical proximity with the rest of the SCF. Besides acting as a component of SCF complexes, FBPs are involved in DNA replication, transcription, cell differentiation and cell death. This review will highlight the recent literature on three well characterized FBPs SKP2, Fbw7, and beta-TRCP. In particular, we will focus on the involvement of these deregulated FBPs in the progression and development of various human cancers. We will also highlight some novel substrates recently identified for these FBPs.
10.1016/j.semcancer.2015.09.008
Emerging role of F-box proteins in the regulation of epithelial-mesenchymal transition and stem cells in human cancers.
Song Yizuo,Lin Min,Liu Yi,Wang Zhi-Wei,Zhu Xueqiong
Stem cell research & therapy
Emerging evidence shows that epithelial-mesenchymal transition (EMT) plays a crucial role in tumor invasion, metastasis, cancer stem cells, and drug resistance. Data obtained thus far have revealed that F-box proteins are critically involved in the regulation of the EMT process and stem cell differentiation in human cancers. In this review, we will briefly describe the role of EMT and stem cells in cell metastasis and drug resistance. We will also highlight how numerous F-box proteins govern the EMT process and stem cell survival by controlling their downstream targets. Additionally, we will discuss whether F-box proteins involved in drug resistance are associated with EMT and cancer stem cells. Targeting these F-box proteins might be a potential therapeutic strategy to reverse EMT and inhibit cancer stem cells and thus overcome drug resistance in human cancers.
10.1186/s13287-019-1222-0