Drug discovery in the ubiquitin–proteasome system

Nalepa, Grzegorz; Rolfe, Mark; Harper, J. Wade

doi:10.1038/nrd2056

Cited by 560 publications

(494 citation statements)

References 162 publications

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“…Targeting of the ubiquitin-proteasome system for pharmaceutical intervention through proteasome inhibition has been successful in the treatment of multiple myeloma and relapsed mantlecell lymphoma [114,115]. Inhibition of CRL activation has become a promising way to treat cancer.…”

Section: Sidebar C | Pharmaceutical Inhibition Of Cullin-ring E3 Ubiqmentioning

confidence: 99%

Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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Cullin-RING E3 ubiquitin ligases (CRLs) control a plethora of biological pathways through targeted ubiquitylation of signalling proteins. These modular assemblies use substrate receptor modules to recruit specific targets. Recent efforts have focused on understanding the mechanisms that control the activity state of CRLs through dynamic alterations in CRL architecture. Central to these processes are cycles of cullin neddylation and deneddylation, as well as exchange of substrate receptor modules to re-sculpt the CRL landscape, thereby responding to the cellular requirements to turn over distinct proteins in different contexts. This review is focused on how CRLs are dynamically controlled with an emphasis on how c ullin neddylation cycles are integrated with receptor exchange. Keywords: cullin; ubiquitin; Nedd8; COP9 signalosome; E3 ligase; CAND1 EMBO reports (2013) 14, 1050-1061 published online 15 November 2013; doi:10.1038/embor.2013 See the Glossary for abbreviations used in this article. IntroductionThe proteome is constantly remodelled to suit the needs of the cell, through both synthesis and turnover. Protein turnover is controlled through two main systems: the ubiquitin-proteasome system (UPS) and lysosomal degradation system, including autophagy. Although selective autophagy can provide a means by which to control the abundance of particular organelles and even single proteins, it is best understood as a means to control bulk turnover of cellular components [1]. Conversely, the UPS is a particularly versatile and highly regulated system [2] that allows selective turnover of individual regulatory proteins, even when they are incorporated into higher-order multiprotein assemblies. On the one hand, the entire population of a given protein targeted by the UPS might be subject to rapid tagging with ubiquitin and degradation by the proteasome. On the other hand, the UPS might control the degradation of only a small pool of a particular target protein, for example the population of a protein that has been phosphorylated by an upstream pathway. Thus, the UPS functions in space and time to sculpt the proteome and to control the abundance of active or inactive forms of signalling complexes and cellular machines. As illustrated in this Review, the UPS machinery that controls turnover of a wide swathe of the p roteome is itself dynamically regulated through many mechanisms.The tagging of proteins with particular types of ubiquitin chains serves to mark them for proteasomal degradation. This process occurs through an E1 (ubiquitin-activating enzyme)-E2 (ubiquitinconjugating enzyme)-E3 (ubiquitin ligase) cascade [3][4][5][6][7]. E3 plays a central role in substrate targeting by binding directly to the substrate and presenting target lysine residues to receive ubiquitin from the E2, in the case of RING E3s, or from a ubiquitin-charged cysteine residue in HECT and RBR E3s [6,[8][9][10]. Cullin-RING E3 ubiquitin ligases (CRLs), which were first discovered almost two decades ago [11][12][13], are a superfamily of RING E3...

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Section: Sidebar C | Pharmaceutical Inhibition Of Cullin-ring E3 Ubiqmentioning

confidence: 99%

Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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“…8,9 Genetic analysis of proteasome function is also of clinical importance as proteasome inhibition may be used as potential antitumor strategy, especially for treatment of multiple myeloma. [10][11][12][13] Autophagy is characterized by the formation of doublemembrane vesicles termed autophagosomes. 14,15 During autophagosome maturation, cytosolic proteins and entire organelles are trapped and delivered to the lysosome for degradation.…”

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confidence: 99%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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“…Cancer is a leading cause of death, accounting for 8.2 million deaths worldwide announced by the WHO. Ubiquitin-proteasome degradation process plays a crucial role in the cell cycle progression and formation of cancer tumours [3,4]. In the G-phase of cell cycle, the negative regulation of cyclin-dependent kinases, affects the ubiquitination and phosphorylation process that leads to tumour formation [5,6].…”

Section: Introductionmentioning

confidence: 99%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

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Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

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Drug discovery in the ubiquitin–proteasome system

Cited by 560 publications

References 162 publications

Building and remodelling Cullin–RING E3 ubiquitin ligases

Building and remodelling Cullin–RING E3 ubiquitin ligases

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

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