An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

Soucy, Teresa A.; Smith, Peter G.; Milhollen, Michael A.; Berger, Allison; Gavin, James M.; Adhikari, Subash; Brownell, James E.; Burke, Kristine; Cardin, David P.; Critchley, Stephen; Cullis, Courtney; Doucette, Amanda; Garnsey, James; Gaulin, Jeffrey L.; Gershman, Rachel E.; Lublinsky, Anna R.; McDonald, Alice; Mizutani, Hirotake; Narayanan, Usha; Olhava, Edward J.; Peluso, Stéphane; Rezaei, Mansoureh; Sintchak, Michael D.; Talreja, Tina; Thomas, Michael; Traore, Tary; Vyskočil, Štěpán; Weatherhead, Gabriel S.; Yu, Jie; Zhang, Julie; Dick, Lawrence R.; Claiborne, Christopher F.; Rolfe, Mark; Bolen, Joseph B.; Langston, Steven

doi:10.1038/nature07884

Cited by 1,725 publications

(2,067 citation statements)

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“…To confirm that the binding between Fbxl17 and Sufu was not due to spurious interaction due to Fbxl17 overexpression, we isolated endogenous Sufu after treating cells with an inhibitor of NAE (Nedd8‐activating enzyme) (MLN4924) (Soucy et al , 2009). This treatment blocks cullin neddylation required for the activity of SCF ubiquitin ligases (Ohh et al , 2002).…”

Section: Resultsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Section: Resultsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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“…The MLN4924 induced toxicity in proliferating cells, is mainly due to the resulting S-phase arrest 11 . We tested the effect of p53 and RPL11 knockdown on cell cycle progression ( The opposite effect was observed upon RPL11 knockdown, which reduced both the MLN4924-induced accumulation of cells in S-phase and cytotoxicity (Fig.…”

Section: Differential Roles Of Rpl11 and P53 In Mln4924-induced Accummentioning

confidence: 99%

“…This knowledge combined with the fact that the inhibitor of the proteasome, bortezomib (Velcade ® ), is used for the treatment of various types of myeloma and lymphoma, prompted development of specific inhibitors of the NEDD8 machinery 4,10 . MLN4924 is a small molecule that specifically inhibits the NEDD8 pathway 11,12 . Treatment of tumour cells with MLN4924 can induce apoptosis, and in vivo MLN4924 shows anti-tumour activity in mice harbouring human xenografts for solid and hematologic tumours 11 .…”

Section: Introductionmentioning

confidence: 99%

“…MLN4924 is a small molecule that specifically inhibits the NEDD8 pathway 11,12 . Treatment of tumour cells with MLN4924 can induce apoptosis, and in vivo MLN4924 shows anti-tumour activity in mice harbouring human xenografts for solid and hematologic tumours 11 . These encouraging preclinical studies with MLN4924 provided the rationale for early phase clinical studies 1,4 .…”

Section: Introductionmentioning

confidence: 99%

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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

et al. 2015

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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway Bailly, A.; Perrin, A.; Bou Malhab, L. J.; Pion, E.; Larance, M.; Nagala, M.; Smith, P.; O'Donohue, M.-F.; Gleizes, P.-E.; Zomerdijk, Josephus; Lamond, Angus; Xirodimas, D. P. Published in: Oncogene DOI:10.1038/onc.2015.104 Publication date: 2016 Document VersionPeer reviewed version Link to publication in Discovery Research Portal Citation for published version (APA):Bailly, A., Perrin, A., Bou Malhab, L. J., Pion, E., Larance, M., Nagala, M., ... Xirodimas, D. P. (2016). The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Oncogene, 35(4), 415-426. DOI: 10.1038415-426. DOI: 10. /onc.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

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“…Early studies demonstrated that cullin neddylation is required for efficient ubiquitylation and/or turnover of CRL substrates in vivo, which has been borne out through the development of MLN4924, a small-molecule inhibitor of NAE [14,[48][49][50]. Inhibition of CRL activity by MLN4924 results in accumulation of a host of CRL targets [14,43,51,52].Structural and biochemical studies revealed a complex mechanism underlying cullin neddylation that involves dual E3 activity and co-translational modification of neddylation E2s to strongly activate the transfer of NEDD8 to the cullin [39,44,53,54]. Early studies indicated that UBC12 can neddylate CUL1 in vitro in a manner that requires RBX1 [55][56][57] For simplicity, therefore, we refer to Cdc53 as yeast CUL1 throughout.…”

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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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An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

Cited by 1,725 publications

References 46 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

Building and remodelling Cullin–RING E3 ubiquitin ligases

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