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Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants.

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.

SUBMITTER: Mukherjee H

PROVIDER: S-EPMC4652655 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants.

Mukherjee Herschel H Chan Kok-Ping KP Andresen Vibeke V Hanley Mariah L ML Gjertsen Bjørn Tore BT Myers Andrew G AG

ACS chemical biology 20150105 3

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, includ ...[more]

PMID: 25531824

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Project description:BackgroundPharmacokinetic natural product-drug interactions (NPDIs) occur when botanical or other natural products are co-consumed with pharmaceutical drugs. With the growing use of natural products, the risk for potential NPDIs and consequent adverse events has increased. Understanding mechanisms of NPDIs is key to preventing or minimizing adverse events. Although biomedical knowledge graphs (KGs) have been widely used for drug-drug interaction applications, computational investigation of NPDIs is novel. We constructed NP-KG as a first step toward computational discovery of plausible mechanistic explanations for pharmacokinetic NPDIs that can be used to guide scientific research.MethodsWe developed a large-scale, heterogeneous KG with biomedical ontologies, linked data, and full texts of the scientific literature. To construct the KG, biomedical ontologies and drug databases were integrated with the Phenotype Knowledge Translator framework. The semantic relation extraction systems, SemRep and Integrated Network and Dynamic Reasoning Assembler, were used to extract semantic predications (subject-relation-object triples) from full texts of the scientific literature related to the exemplar natural products green tea and kratom. A literature-based graph constructed from the predications was integrated into the ontology-grounded KG to create NP-KG. NP-KG was evaluated with case studies of pharmacokinetic green tea- and kratom-drug interactions through KG path searches and meta-path discovery to determine congruent and contradictory information in NP-KG compared to ground truth data. We also conducted an error analysis to identify knowledge gaps and incorrect predications in the KG.ResultsThe fully integrated NP-KG consisted of 745,512 nodes and 7,249,576 edges. Evaluation of NP-KG resulted in congruent (38.98% for green tea, 50% for kratom), contradictory (15.25% for green tea, 21.43% for kratom), and both congruent and contradictory (15.25% for green tea, 21.43% for kratom) information compared to ground truth data. Potential pharmacokinetic mechanisms for several purported NPDIs, including the green tea-raloxifene, green tea-nadolol, kratom-midazolam, kratom-quetiapine, and kratom-venlafaxine interactions were congruent with the published literature.ConclusionNP-KG is the first KG to integrate biomedical ontologies with full texts of the scientific literature focused on natural products. We demonstrate the application of NP-KG to identify known pharmacokinetic interactions between natural products and pharmaceutical drugs mediated by drug metabolizing enzymes and transporters. Future work will incorporate context, contradiction analysis, and embedding-based methods to enrich NP-KG. NP-KG is publicly available at https://doi.org/10.5281/zenodo.6814507. The code for relation extraction, KG construction, and hypothesis generation is available at https://github.com/sanyabt/np-kg.

Dataset Information

Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants.

Publications

Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants.

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