ArticleACS chemical biology2015
Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 30 citations in OpenAlex.
- The emerging synergy of experimental and computational approaches for therapeutic modulation of biomolecular condensates.SLAS discovery : advancing life sciences R & D · 2026Review
- Targeting protein disorder: the next hurdle in drug discovery.Nature reviews. Drug discovery · 2025Review
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- Hypoxia upregulates the expression of PD-L1 via NPM1 in breast cancer.Journal for immunotherapy of cancer · 2025Article
- Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates.BMC biology · 2025Review
- Could Targeting NPM1c+ Misfolding Be a Promising Strategy for Combating Acute Myeloid Leukemia?International journal of molecular sciences · 2024Review
- Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.Journal of hematology & oncology · 2023Review
- Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment.Cancer research · 2023Review
- DDX24 Mutation Alters NPM1 Phase Behavior and Disrupts Nucleolar Homeostasis in Vascular Malformations.International journal of biological sciences · 2023Article
- Modulating biomolecular condensates: a novel approach to drug discovery.Nature reviews. Drug discovery · 2022Review
- Review
- Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα-NF-κB p65 Complex.Frontiers in pharmacology · 2022Article
- Nucleophosmin in Its Interaction with Ligands.International journal of molecular sciences · 2020Review
- Nucleolar Stress: hallmarks, sensing mechanism and diseases.Cell stress · 2018Review
- Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia.Scientific reports · 2017Article
- Chromosomal passenger complex hydrodynamics suggests chaperoning of the inactive state by nucleoplasmin/nucleophosmin.Molecular biology of the cell · 2017Article
- Heteroatom-Heteroatom Bond Formation in Natural Product Biosynthesis.Chemical reviews · 2017Review
- Drug Repurposing for the Treatment of Acute Myeloid Leukemia.Frontiers in medicine · 2017Review
- Anti-proliferative activity of the NPM1 interacting natural product avrainvillamide in acute myeloid leukemia.Cell death & disease · 2016Article
- A redox mechanism underlying nucleolar stress sensing by nucleophosmin.Nature communications · 2016Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Nucleophosmin (NPM1) is a multifunctional phosphoprotein localized predominantly within the nucleoli of eukaryotic cells. Mutations within its C-terminal domain are frequently observed in patients with acute myeloid leukemia (AML), are thought to play a key role in the initiation of the disease, and result in aberrant, cytoplasmic localization of the mutant protein. We have previously shown that the electrophilic antiproliferative natural product (+)-avrainvillamide (1) binds to proteins, including nucleophosmin, by S-alkylation of cysteine residues. Here, we report that avrainvillamide restores nucleolar localization of certain AML-associated mutant forms of NPM1 and provide evidence that this relocalization is mediated by interactions of avrainvillamide with mutant NPM1 and exportin-1 (Crm1). Immunofluorescence and mass spectrometric experiments employing a series of different NPM1 constructs suggest that a specific interaction between avrainvillamide and Cys275 of certain NPM1 mutants mediates the relocalization of these proteins to the nucleolus. Avrainvillamide treatment is also shown to inhibit nuclear export of Crm1 cargo proteins, including AML-associated NPM1 mutants. We also observe that avrainvillamide treatment displaces Thr199-phosphorylated NPM1 from duplicated centrosomes, leads to an accumulation of supernumerary centrosomes, and inhibits dephosphorylation of Thr199-phosphorylated NPM1 by protein phosphatase 1. Avrainvillamide is the first small molecule reported to relocalize specific cytoplasmic AML-associated NPM1 mutants to the nucleolus, providing an important demonstration of principle that small molecule induction of a wild-type NPM1 localization phenotype is feasible in certain human cancer cells.
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