The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy

Soucy, T. A.; Dick, L. R.; Smith, P. G.; Milhollen, M. A.; Brownell, J. E.

doi:10.1177/1947601910382898

Cited by 225Ubiquitin and proteasome pathwaysCancer-related Molecular PathwaysProtein Degradation and Inhibitors

The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy

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Soucy, T. A., Dick, L. R., Smith, P. G., Milhollen, M. A., Brownell, J. E.·2010·Genes & Cancer

DOI 10.1177/1947601910382898PMC PMC3092238

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Abstract

Cancer cells depend on signals that promote cell cycle progression and prevent programmed cell death that would otherwise result from cumulative, aberrant stress. These activities require the temporally controlled destruction of specific intracellular proteins by the ubiquitin-proteasome system (UPS). To a large extent, the control points in this process include a family of E3 ubiquitin ligases called cullin-RING ligases (CRLs). The ligase activity of these multicomponent complexes requires modification of the cullin protein situated at their core with a ubiquitin-like protein called NEDD8. Neddylation results in conformational rearrangements within the CRL, which are necessary for ubiquitin transfer to a substrate. The NEDD8 pathway thus has a critical role in mediating the ubiquitination of numerous CRL substrate proteins involved in cell cycle progression and survival including the DNA replication licensing factor Cdt-1, the NF-κB transcription factor inhibitor pIκBα, and the cell cycle regulators cyclin E and p27. The initial step required for attachment of NEDD8 to a cullin is catalyzed by the E1, NEDD8-activating enzyme (NAE). The first-in-class inhibitor of NAE, MLN4924, has been shown to block the activity of NAE and prevent the subsequent neddylation of cullins. Preclinical studies have demonstrated antitumor activity in various solid tumors and hematological malignancies, and preliminary clinical data have shown the anticipated pharmacodynamic effects in humans. Here, we review the NEDD8 pathway, its importance in cancer, and the therapeutic potential of NAE inhibition.

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Cullin-based ubiquitin ligase activity is stimulated by neddylation and downregulated by deneddylation mediated by the COP9 signalosome.
“Cullin-based ubiquitin ligase activity is stimulated by neddylation (i.e., NEDD8 conjugation) to cullin and downregulated by deneddylation mediated by the COP9 signalosome6,7.”
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Authors: Soucy, T. A., Dick, L. R., Smith, P. G., Milhollen, M. A., & Brownell, J. E.
Affiliations: Takeda Oncology (United States) (US)
Corresponding author: Soucy, T. A.
ORCID: Dick, L. R.
Smith, P. G.
Milhollen, M. A.
Brownell, J. E.
Venue: Genes & Cancer
Publisher: SAGE Publications
Published: 2010-07-01
Volume: 1
Issue: 7
Pages: 708-716
ISSN: 1947-6019 (ISSN-L)
1947-6027
DOI: 10.1177/1947601910382898
PMC: PMC3092238
OpenAlex: W2147045066
Cited by: 225
References: 127
Citations by year: 2026: 7 · 2025: 5 · 2024: 12 · 2023: 15 · 2022: 17 · 2021: 13 · 2020: 24 · 2019: 9 · 2018: 14 · 2017: 10 · 2016: 14 · 2015: 19 · 2014: 17 · 2013: 22 · 2012: 24
FWCI: 6.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Genes & Cancer (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Utah Agricultural Experiment Station
Takeda Oncology
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords: neddylation, cullin-RING ligases, NEDD8-activating enzyme, MLN4924, ubiquitin-proteasome system, E3 ubiquitin ligase, cyclin E, p27, cell cycle regulation, cancer therapy, hematologic malignancies, solid tumors

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The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy

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