Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets

Bedford, Lynn; Lowe, James; Dick, Lawrence R.; Mayer, R. John; Brownell, James E.

doi:10.1038/nrd3321

Cited by 483 publications

(415 citation statements)

References 173 publications

(147 reference statements)

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“…CRL substrate receptors (SRs) CDC4/FBXW7 and SKP2 have also been targeted for small-molecule inhibition [122][123][124]. As more is understood about these pathways, we envision that the inhibition of CRLs and individual SRs is a promising and growing field of drug discovery [33]. …”

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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“…Although the UPS is a popular target in cancer, where its activity is reduced by compounds such as bortezomib (Velcade, Millenium Pharmaceuticals) 149 , upregulation of proteasomal degradation by a small molecule has only recently been reported 150 . It will be interesting to follow the further development of such compounds and monitor their effects in models of HD and AD, as they are valuable tools for the further validation of the UPS as a therapeutic target.…”

Section: Increasing the Clearance Of Misfolded Proteins: The Ubiquitimentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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“…Moreover, irreversible inhibitors capable of alkylating the active site cysteine are in general reactive to other nucleophiles, especially other thiols (Daviet and Colland, 2008). Accordingly, several members of the JAMM metalloprotease family of DUBs, such as POH1, CSN5, AMSH and BRCC36, have been proposed as alternative candidates for drug targeting in cancer (Bedford et al, 2011).…”

Section: Targeting Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets

Cited by 483 publications

References 173 publications

Building and remodelling Cullin–RING E3 ubiquitin ligases

Building and remodelling Cullin–RING E3 ubiquitin ligases

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Deubiquitinases in cancer: new functions and therapeutic options

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