Abstract |
The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK(+)ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P = 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.
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Authors | Leah C Young, Kathleen M Bone, Peng Wang, Fang Wu, Benjamin A Adam, Samar Hegazy, Pascal Gelebart, Jelena Holovati, Liang Li, Susan E Andrew, Raymond Lai |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 179
Issue 1
Pg. 411-21
(Jul 2011)
ISSN: 1525-2191 [Electronic] United States |
PMID | 21703420
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- DNA-Binding Proteins
- G-T mismatch-binding protein
- Tyrosine
- p80(NPM-ALK) protein
- Protein-Tyrosine Kinases
- MSH2 protein, human
- MutS Homolog 2 Protein
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Topics |
- Cytoplasm
(metabolism)
- DNA Damage
- DNA Mismatch Repair
- DNA-Binding Proteins
(genetics, metabolism)
- Humans
- Immunoenzyme Techniques
- Immunoprecipitation
- Lymphoma, Large B-Cell, Diffuse
(genetics, metabolism, pathology)
- Lymphoma, Large-Cell, Anaplastic
(genetics, metabolism, pathology)
- Microsatellite Instability
- MutS Homolog 2 Protein
(genetics, metabolism)
- Phosphorylation
- Protein Multimerization
- Protein Transport
- Protein-Tyrosine Kinases
(genetics, metabolism)
- Tumor Cells, Cultured
- Tyrosine
(metabolism)
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