ArticleNeoplasia (New York, N.Y.)2011
Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression.
Article in Neoplasia (New York, N.Y.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
96 citing papers in PubMed, 154 citations in OpenAlex.
- Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes.Acta pharmacologica Sinica · 2026Review
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- Neddylation inhibition induces DNA double-strand breaks, hampering tumor growth in vivo, and promotes radiosensitivity in PAX3-FOXO1 rhabdomyosarcoma.Cell death discovery · 2025Article
- MLN4924 inhibits macrophage foam cell formation by enhancing autophagy and regulating metabolic phenotype.Lipids in health and disease · 2025Article
- Protein neddylation in lung tumorigenesis: Target validation and targeted therapy.Fundamental research · 2025Review
- SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation.Cell death & disease · 2025Article
- Inhibiting neddylation: A new strategy for tumor therapy.Journal of pharmaceutical analysis · 2025Review
- Senolytic Prodrugs: A Promising Approach to Enhancing Senescence-Targeting Intervention.Chembiochem : a European journal of chemical biology · 2024Review
- Phase 1 study of NEDD8 activating enzyme inhibitor pevonedistat in combination with chemotherapy in pediatric patients with recurrent or refractory solid tumors (ADVL1615).European journal of cancer (Oxford, England : 1990) · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways.Biomarker research · 2024Review
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions.Journal of hematology & oncology · 2023Review
- Targeting neddylation as a novel approach to lung cancer treatment (Review).International journal of oncology · 2023Review
- NEDD8-conjugating enzyme E2s: critical targets for cancer therapy.Cell death discovery · 2023Review
- Targeting cullin neddylation for cancer and fibrotic diseases.Theranostics · 2023Review
- Pro-senescence neddylation inhibitor combined with a senescence activated β-galactosidase prodrug to selectively target cancer cells.Signal transduction and targeted therapy · 2022Article
- Inhibition of NEDD8 NEDDylation induced apoptosis in acute myeloid leukemia cells via p53 signaling pathway.Bioscience reports · 2022Article
- Article
- Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment.Signal transduction and targeted therapy · 2021Review
36 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
Cullin-RING ubiquitin ligase (CRL), with its founding member of SKP1-Cullins-F-box proteins (SCF) E3 ubiquitin ligase, is the largest family of E3 ligases, which requires cullin neddylation for its activation. Recently, an inhibitor of NEDD8 activating enzyme (NAE), MLN4924, was reported to block cullin neddylation and inactivate CRL/SCF E3, resulting in apoptosis induction and tumor suppression both in vitro and in vivo. We report here that apoptosis is not the sole mechanism by which MLN4924 suppresses tumor cell growth because apoptosis is moderately induced by the drug in some cancer cell lines and drug-induced growth suppression is only partially blocked by a pan-caspase inhibitor, z-VAD. MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence-associated β-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. The senescence occurs in the manner independent of pRB/p16 and p53, but dependent on p21, a known substrate of CRL/SCF E3s and a mediator of senescence, which accumulates on CRL/SCF inactivation by MLN4924. Furthermore, MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. Our study reveals a novel mechanism of MLN4924 action and showed that MLN4924 could be further developed as an effective anticancer agent by inducing apoptosis and irreversible senescence.
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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.