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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    • "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.
    12/2014; 3. DOI:10.1016/j.redox.2014.10.006
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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.
    Proteome Science 08/2013; 11(1):39. DOI:10.1186/1477-5956-11-39 · 1.73 Impact Factor
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    • "Ubiquitin is responsible for the conjugation of proteins, marking them for selective degradation via the ubiquitin-proteasome system 26S, a process that is essential in the response to cellular stress. These proteins, however, act through ubiquitination, changing the function, the location and/or the traffic protein, or are targeted for destruction by the 26S proteasome [46]. "
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    ABSTRACT: Background The fungus Paracoccidioides spp is the agent of paracoccidioidomycosis (PCM), a pulmonary mycosis acquired by the inhalation of fungal propagules. Paracoccidioides malate synthase (PbMLS) is important in the infectious process of Paracoccidioides spp because the transcript is up-regulated during the transition from mycelium to yeast and in yeast cells during phagocytosis by murine macrophages. In addition, PbMLS acts as an adhesin in Paracoccidioides spp. The evidence for the multifunctionality of PbMLS indicates that it could interact with other proteins from the fungus and host. The objective of this study was to identify and analyze proteins that possibly bind to PbMLS (PbMLS-interacting proteins) because protein interactions are intrinsic to cell processes, and it might be possible to infer the function of a protein through the identification of its ligands. Results The search for interactions was performed using an in vivo assay with a two-hybrid library constructed in S. cerevisiae; the transcripts were sequenced and identified. In addition, an in vitro assay using pull-down GST methodology with different protein extracts (yeast, mycelium, yeast-secreted proteins and macrophage) was performed, and the resulting interactions were identified by mass spectrometry (MS). Some of the protein interactions were confirmed by Far-Western blotting using specific antibodies, and the interaction of PbMLS with macrophages was validated by indirect immunofluorescence and confocal microscopy. In silico analysis using molecular modeling, dynamics and docking identified the amino acids that were involved in the interactions between PbMLS and PbMLS-interacting proteins. Finally, the interactions were visualized graphically using Osprey software. Conclusion These observations indicate that PbMLS interacts with proteins that are in different functional categories, such as cellular transport, protein biosynthesis, modification and degradation of proteins and signal transduction. These data suggest that PbMLS could play different roles in the fungal cell.
    BMC Microbiology 05/2013; 13(1):107. DOI:10.1186/1471-2180-13-107 · 2.73 Impact Factor
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