ArticleProceedings of the National Academy of Sciences of the United States of America2000
A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
102 citing papers in PubMed, 243 citations in OpenAlex.
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- The role of ubiquitin system in ageing-related diseases and potential therapeutic opportunities.Molecular biomedicine · 2026Review
- Targeting neddylation as a novel approach to lung cancer treatment (Review).International journal of oncology · 2023Review
- Review
- Quantitative analyses for effects of neddylation on CRL2Protein science : a publication of the Protein Society · 2021Article
- NUB1 and FAT10 Proteins as Potential Novel Biomarkers in Cancer: A Translational Perspective.Cells · 2021Review
- Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer.Cancers · 2021Review
- Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer.Breast cancer research and treatment · 2021Article
- Small molecules targeting the NEDD8·NAE protein-protein interaction.Chemical science · 2020Article
- The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway.Molecular and cellular biology · 2020Review
- Article
- Transfer of ubiquitin protein caught in the act.Nature · 2020Article
- Neddylation inhibitor, MLN4924 suppresses angiogenesis in huvecs and solid cancers:American journal of cancer research · 2020Article
- The NEDD8-activating enzyme inhibitor MLN4924 induces DNA damage in Ph+ leukemia and sensitizes for ABL kinase inhibitors.Cell cycle (Georgetown, Tex.) · 2019Article
- Evolutionary Approach of Intrinsically Disordered CIP/KIP Proteins.Scientific reports · 2019Article
- Characterisation of cellular effects ofBiology open · 2018Article
- CKS1 expression in melanocytic nevi and melanoma.Oncotarget · 2018Article
- Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924).Investigational new drugs · 2017Article
- The Protein Neddylation Pathway in Trypanosoma brucei: FUNCTIONAL CHARACTERIZATION AND SUBSTRATE IDENTIFICATION.The Journal of biological chemistry · 2017Article
42 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Temporal control of p27(Kip1) (p27) degradation imposes periodicity in its activity during cell cycle progression and its accumulation during cell cycle exit. Degradation of p27 is initiated by phosphorylation of p27 at Thr-187, which marks the protein for ubiquitination by SCF(Skp2) and subsequent proteolysis by the 26S proteasome. Here we show that the p27 ubiquitination activity in cell extracts depends on the presence of the ubiquitin-like protein Nedd8 and enzymes that catalyze Nedd8 conjugation to proteins. Moreover, we show that reconstitution of the p27 ubiquitination activity of recombinant SCF(Skp2) also requires Nedd8 conjugation pathway components. Inactivation of the Nedd8 conjugation pathway by a dominant negative mutant of the Nedd8-conjugating enzyme Nce1/Ubc12 blocks the ubiquitination and degradation of p27 in cell extracts. Consistent with a role in cell-cycle progression, Nedd8 is expressed in proliferating cells and is itself down-regulated upon cellular differentiation. These results suggest that the Nedd8 conjugation pathway may regulate the turnover of p27(Kip1), independently of p27 phosphorylation, and further establishes the identity of protein components involved in p27 ubiquitination. Finally, these findings provide a direct demonstration of a function for Nedd8 in a biological process.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.