Elsevier

Seminars in Cancer Biology

Volume 36, February 2016, Pages 18-32
Seminars in Cancer Biology

Review
Involvement of F-BOX proteins in progression and development of human malignancies

https://doi.org/10.1016/j.semcancer.2015.09.008Get rights and content

Abstract

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.

Introduction

Timely and spatial regulated mechanism based on abundance and destruction of multi-protein molecular machines, which regulate fundamental cellular functions, is critical for maintaining systemic homeostasis. Ubiquitin Proteasome System (UPS) is an evolutionary conserved protein degradation mechanism that is involved in various physiological responses like cell cycle control, DNA replication, transcription, cell signaling, as well as DNA repair and cell death [1], [2], [3]. Dysregulation of ubiquitin-dependent proteolysis has been broadly suggested in progression and development of cancer, as the UPS plays critical roles by catalyzing many governing proteins in key signaling pathways throughout the cell [4], [5], [6]. Polyubiquitin formation is carried out in three subsequent strides by the various genes of ubiquitin activating (E1), ubiquitin-conjugating (E2) and ubiquitin ligase (E3) enzymes [7]. In the first step entire cellular pool of ubiquitin (Ub) is activated by the E1 enzyme by the creation of thioester linkage between Ub and the cysteine residues of E1. Then, activated Ub is conjugated to an active cysteine side chain of ubiquitin-carrier protein, the E2 enzyme. In the third step catalyzed by E3 enzyme, the C-terminus of ubiquitin moities are linked through an amide-isopeptide to a ɛ-amino group of the lysine residue in the substrate protein (Fig. 1). This kind of modification to a substrate through sequential conjugation of ubiquitin on the lysine residue at position 48, leads to protein degradation [8].

Although inhibition of E1 enzyme has been proposed as a strategy for anti-cancer therapy [9], there is no direct evidence that the two discovered human E1 activating enzymes are involved in carcinogenesis, and only a few reports from 38 known E2 conjugating enzymes are pointing out their role in malignant transformation [8], [9]. In contrast, the human genome possibly encodes up to 1000 E3 ligases and many of them have been broadly implicated in the development of cancer, mostly due to the fact that a high variability of different E3 enzymes is a key feature responsible for substrate specificity [10], [11]. From the two primary classes of ubiquitin ligases, HECT domain (Homologous to E6-AP Carboxy Terminus-type E3s) and RING domain (Really Interesting New Gene-type E3s), the later one constitutes the largest superfamily of more than 600 E3s in mammalian cells extensively studied over past years [12], [13]. Perhaps the best characterized RING-type E3s that occur are multisubunit assemblies containing cullin-family scaffold proteins (Cullin-RING Ligases – CRLs). A prototypical example of E3 enzyme based on the cullin scaffold is the SCF ubiquitin ligase complex. This E3 ligase is composed of three primary and invariable components – SKP1 (S-phase kinase-associated protein-1), CUL1 (Cullin), and RBX1/ROC1 and an FBP, a variable element capable of substrate selection [14], [15]. Among various regulatory proteins, FBPs are essential functional components of UPS. FBPs mainly operate by regulating substrates in multiple pathways that are critical for the biological functions such as cell division, cell growth, cell survival and death, signaling responses, and development and differentiation [16], [17], [18]. Scientific evidence gathered over time strongly argues that any abnormality in FBPs results in cancer by either genomic instability or by uncontrolled proliferation. FBPs are extensively studied in perspective of cell proliferation even though FBPs are known to be involved in varied biological pathways. As cell proliferation is the primary target for any cancer study, therefore the role of FBP has been widely seen in the context of cancer biology [19]. The members of FBPs like FBXW7, SKP2, and βTrCP, have been thoroughly characterized in terms of their biological functions [20], [21]. Keeping in mind the role played by FBPs, it becomes immensely important to study the role of other members of FBPs in cancer as well as in other diseases. Therefore, this review focuses mainly on the well characterized FBPs that are playing an important role in the pathology of human malignancies.

Section snippets

The FBPs families

FBPs are the important class of proteins that are involved in cellular functions such as cell division and cell signaling. They derive their name from the presence of at least one F-box domain, which was primarily discovered in cyclin F as a characteristic 50-amino-acid region [22] (Fig. 2). Other homology domains, in addition to F-box domain, have been found in FBPs and are responsible for the substrate recognition and binding. Based on the types of the substrate-interaction domains, 69 FBPs

FBXW7

FBXW7 is a member of FBP family that displays a significant tumor suppressive role in many malignancies. It plays the important role in various cellular and physiological functions such as in cell cycle progression, cell growth, apoptosis, invasion and drug resistance [28]. FBXW7 prevents tumor development by facilitating the destruction of oncogenic proteins via involving ubiquitination and proteasomal pathways [28]. FBXW7 mediated tumor suppressive effects occurs by negative regulation of

SKP2

The SKP2 is an SCF ubiquitin ligase critical for cell cycle progression and cell proliferation. SKP2 is found to be the rate-limiting element of the SCF protein complex that degrades tumor suppressor protein p27 via ubiquitylation [56], [57], [58]. SKP2 recognizes phosphorylated p27Kip1 in S-phase with the cooperation of SKP1 and leads to its degradation along with the other tumor suppressor genes, thus considered as an oncogene. There are other numerous studies showing the participation of

FBPs: defined classes

Among all the FBPs discovered, only SKP2, FBXW7 and β-TrCP are well studied and characterized with respect to their substrates as well as their functionality. There are still a large number of FBPs that have been identified but yet to be characterized in detail.

Breast cancer

Malignancy of the breast is the most common cancer in female worldwide and second most common cause of cancer-related mortality after pulmonary disease [96]. Despite the introduction of newer useful therapeutic modalities in the management of breast cancer, it remains a fundamental cause of cancer morbidity and mortality. This is due to either development of resistance to newer drugs or relapse after initial response leading to tumor progression, metastasis and finally resulting in

FBPs and other cancers

The role of FBPs has been reported in many other cancers such as pancreatic cancer, hepatocellular carcinoma, thyroid cancer, ovarian cancer and renal cell carcinoma. In these cancers, the study about FBPs has been very modest and here we review most of the related literature. Despite recent improvements, overall survival for advanced adenocarcinoma of the pancreas continues to be poor. Previous studies reported the mutational status of BRAF and FBXW7 in relation to two distinct subsets of

FBPs as candidate for therapeutic target

As many studies have established the role of FBPs as tumor-suppressors or oncogenic functions, there is a precedent to explore FBPs as therapeutic targets for the prevention and treatment of various malignancies. Extensive studies establishing the role of SKP2 in different cancers makes it a promising therapeutic target. High-throughput screening identified many small molecules acting as SKP2 inhibitors which mainly block SKP2 E3 ligase activity [87], [206]. These small molecule inhibitors have

Conclusion and future perspective

The current understanding demonstrates that FBPs play essential role in tumorigenesis mainly by regulating the substrate turnover which could be both in E3 ligase activity-dependent or activity-independent manner [210], [211], [212]. Four FBPs, namely FBXW7, SKP2, β-TRCP1 and β-TRCP2, have been studied among the pool of 69 FBPs identified. Little is known of the remaining members of FBP family. Interestingly, the inhibitors of SKP2 have been shown to have therapeutic potential. This should

Conflict of interest

No conflicts of interest exist.

Funding

The authors declare that they have no competing financial interest.

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