Burger AM, Seth AKThe ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer 40: 2217-2229

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
European Journal of Cancer (Impact Factor: 5.42). 11/2004; 40(15):2217-29. DOI: 10.1016/j.ejca.2004.07.006
Source: PubMed


The highly conserved eukaryotic ubiquitin-proteasome system (UP-S) plays a pivotal role in protein homeostasis and is critical in regulating normal and cancer-related cellular processes. The hierarchical nature of the UP-S provides a rich source of molecular targets for specific intervention and has therefore arisen as a promising approach to innovative anticancer therapies. The first in class proteasome inhibitory agent Bortezomib (Velcade) has recently obtained regulatory approval for the treatment of multiple myeloma. Ubiquitin-mediated degradation is a complex process that is comprised of well defined steps involving ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Although a single E1 activates the ubiquitin conjugation machinery, a large number of E2 conjugating enzymes and E3 ligases are now known to exist. Proteins tagged with ubiquitin are subsequently recognised by the proteasome for digestion and fragmentation. The enzymatic nature, multitude of E3s and their specific substrate recognition predestines them as therapeutic targets. This article will review known inhibitors of the proteasome and their molecular mechanisms as well as ongoing developments and promising avenues for targeting substrate-specific E3 ligases that are likely to yield a new class of therapeutics that will serve and complement the armamentarium of anticancer drugs.

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Available from: Arun Seth, Mar 11, 2014
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    • "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 "
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    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.
    Full-text · Article · Sep 2015 · Seminars in Cancer Biology
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    • "Others report that in vivo treatment with a gene vector that expresses the transcription factor EB (TFEB), an important regulator of autophagy and lysosome biogenesis [13], also activates the autophagic pathway to enhance α-1AT removal. The proteasome inhibitor, bortezomib (Velcade s ) is used with other anti-cancer drugs as an effective treatment for the hematological malignancy, multiple myeloma [14] [15] [16]. In the absence of disease, autophagy and the UPS maintain normal cell function by degrading larger molecules to smaller ones, which are further broken down to generate ATP. "
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    ABSTRACT: In this review, we describe research findings on the effects of alcohol exposure on two major catabolic systems in liver cells: the ubiquitin–proteasome system (UPS) and autophagy. These hydrolytic systems are not unique to liver cells; they exist in all eukaryotic tissues and cells. However, because the liver is the principal site of ethanol metabolism, it sustains the greatest damage from heavy drinking. Thus, the focus of this review is to specifically describe how ethanol oxidation modulates the activities of the UPS and autophagy and the mechanisms by which these changes contribute to the pathogenesis of alcohol-induced liver injury. Here, we describe the history and the importance of cellular hydrolytic systems, followed by a description of each catabolic pathway and the differential modulation of each by ethanol exposure. Overall, the evidence for an involvement of these catabolic systems in the pathogenesis of alcoholic liver disease is quite strong. It underscores their importance, not only as effective means of cellular recycling and eventual energy generation, but also as essential components of cellular defense.
    Full-text · Article · Dec 2014
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    • "The ubiquitin pathway has been implicated in several forms of malignancy through the degradation of tumor suppressor proteins [26]. In uterine cervical carcinomas, the tumor-suppressor protein p53 is tagged by the human papilloma virus (HPV) oncoprotein E6 for ubiquitin-mediated degradation resulting in transformed cells [27]. "
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    ABSTRACT: Post treatment minimal residual disease (MRD) determination contributes to impending relapse prediction, chemotherapy response and clinical outcomes assessment, guiding clinicians to develop reasonable and effective individual chemotherapy options after induction/consolidation. This study was to identify serum candidate peptides for monitoring adult acute myeloid leukemia (AML) MRD. 47 statistically different expressed peptide peaks were obtained in the molecular weight range of 700-10000 Da. Quick classifier (QC) model had optimal distinction efficiency, in the training set with a sensitivity of 90% and a specificity of 93.33%. Peptides were identified as ubiquitin-like modifier activating enzyme 1(UBA1), isoform 1 of fibrinogen alpha chain precursor and platelet factor 4(PF4). The peptide up-regulated in newly diagnosed AML patients were decreased to the normal level after CR. When refractory & relapsed, relative intensity was elevated again. Results were contrary to down-regulated peptide peaks. Western blot demonstrated that levels of the UBA1 protein did not differ between the leukemia and normal cells. Levels of isoform 1 of fibrinogen alpha chain precursor protein and PF4 protein were both decreased in leukemia cells comparing with normal cells. The serum levels of the PF4 in the newly diagnosed AML patients and healthy controls were significantly different. Further correlation analysis did not indicate the correlated relation between platelet counts and PF4 content, the correlation coefficient was 0.097. Kaplan--Meier analyses of overall survival showed that relative intensity of peptides was correlated with patient's clinical outcome. We speculate the peptides can be used as potential markers for monitoring minimal residual disease and clinical outcome assessment.
    Full-text · Article · Aug 2013 · Proteome Science
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