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Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

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Arregi, Igor Falces Ramos, Jorge [UCL] Olazabal-Herrero, Anne Alonso-Mariño, Marián Taneva, Stefka G. Larijani, Banafshe

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2015
Language Anglais
Journal information "PLoS One" - Vol. 10, no.6, p. e0130610 (2015)
Peer reviewed yes
Publisher Public Library of Science
issn 1932-6203
e-issn 1932-6203
Publication status Publié
Affiliation UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
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Bibliographic reference Arregi, Igor ; Falces Ramos, Jorge ; Olazabal-Herrero, Anne ; Alonso-Mariño, Marián ; Taneva, Stefka G. ; et. al. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport. In: PLoS One, Vol. 10, no.6, p. e0130610 (2015)
Permanent URL http://hdl.handle.net/2078.1/186279