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Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal.
- Source :
-
Oncogene . 7/20/2006, Vol. 25 Issue 31, p4376-4380. 5p. 2 Color Photographs. - Publication Year :
- 2006
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Abstract
- Nucleophosmin (NPM) is a nucleus–cytoplasmic shuttling protein that is implicated in centrosome duplication, cell cycle progression and stress response. At the steady state, NPM localizes mainly in the nucleolus, where it forms a complex with different cellular proteins. One-third of acute myeloid leukemias (AML) are characterized by aberrant cytoplasmic localization of NPM, due to mutations within its last coding exon (exon 12) that cause a frameshift and the formation of novel C-termini. We report here our investigations on the molecular basis for the aberrant localization of mutated NPM. Alignment of the C-terminus of the various NPM mutants revealed the obligatory presence of four amino-acid residues that match a CRM1-dependent nuclear export signal (NES). Single alanine-substitutions at these sites provoked nuclear re-localization, while fusion of the mutated C-terminus to a heterologous nuclear protein induced CRM1-dependent cytoplasmic localization. Molecular characterization of one exceptional AML carrying cytoplasmic NPM and germ line exon 12 revealed a somatic mutation in the splicing donor site of exon 9 that caused the formation of a functional NES. It appears, therefore, that AMLs are frequently characterized by gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.Oncogene (2006) 25, 4376–4380. doi:10.1038/sj.onc.1209453; published online 27 February 2006 [ABSTRACT FROM AUTHOR]
- Subjects :
- *NUCLEOLUS
*LEUKEMIA
*PROTEINS
*AMINO acids
*LEUKEMIA etiology
Subjects
Details
- Language :
- English
- ISSN :
- 09509232
- Volume :
- 25
- Issue :
- 31
- Database :
- Academic Search Index
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 21656014
- Full Text :
- https://doi.org/10.1038/sj.onc.1209453