Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy

Dick, Lawrence R.; Fleming, Paul

doi:10.1016/j.drudis.2010.01.008

Cited by 250 publications

(207 citation statements)

References 48 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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“…Therefore, the ubiquitin signaling pathway, and more specifically, the enzymes involved in both ubiquitination, deubiquitination and proteasome, have been considered a good therapeutic target, and many inhibitors targeting specific enzymes in ubiquitin pathways have been developed as drug candidates for various diseases [16,19]. In particular, Bortezomib, an ubiquitin proteasome system (UPS) inhibitor approved by the US FDA as a cancer drug, supports the druggability of the ubiquitin signaling [20,21]. While the enzymes in the ubiquitin pathways have been recognized as druggable targets [22][23][24], ubiquitin, the main agent of this signaling pathway, has been generally considered as non-druggable.…”

Section: Introductionmentioning

confidence: 99%

An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors

Nguyen

Ghosh

et al. 2016

Biochemical and Biophysical Research Communications

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The ubiquitin pathway plays a critical role in regulating diverse biological processes, and its dysregulation is associated with various diseases. Therefore, it is important to have a tool that can control the ubiquitin pathway in order to improve understanding of this pathway and to develop therapeutics against relevant diseases. We found that Chicago Sky Blue 6B binds directly to the β-groove, a major interacting surface of ubiquitin. Hence, it could successfully inhibit the enzymatic activity of ubiquitin processing enzymes and the binding of ubiquitin to the CXCR4, a cell surface ubiquitin receptor. Furthermore, we demonstrated that this ubiquitin binding chemical could effectively suppress the ubiquitin induced cancer cell migration by blocking ubiquitin-CXCR4 interaction. Current results suggest that ubiquitin binding molecules can be developed as inhibitors of ubiquitin-protein interactions, which will have the value not only in unveiling the biological role of ubiquitin but also in treating related diseases.

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“…The small molecule inhibitor oprozomib (OZ) was used to only inhibit the chymotrypsin-like activity of the proteasome (Fig. 6B) (49). Again, dose-dependent inhibition of the CT-L catalytic site resulted in enhanced recruitment of PA28␥ and PA200 to 20S and 26S proteasomes.…”

Section: Recruitment Of Proteasomal Activators Depends On the Extent mentioning

confidence: 99%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

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The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28␣␤, PA28␥, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28␥ and PA200 to 20S and 26S proteasomes within 2-6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28␥ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of ␤5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28␥ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28␥ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis.The proteasome, one of the main proteolytic systems of the cell, is essential for maintenance of protein homeostasis and thus of cellular functions. The proteolytic activity of this multicatalytic protease resides inside the 20S core particle, built of four stacked rings of seven ␣ and ␤ subunits with ␣ 7

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Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy

Cited by 250 publications

References 48 publications

Building and remodelling Cullin–RING E3 ubiquitin ligases

Building and remodelling Cullin–RING E3 ubiquitin ligases

An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

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