Fusion tyrosine kinase NPM-ALK Deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein
| Autor: | 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 |
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| Rok vydání: | 2010 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cytoplasm integumentary system Regular Article Protein-Tyrosine Kinases DNA Mismatch Repair digestive system diseases DNA-Binding Proteins Immunoenzyme Techniques Protein Transport MutS Homolog 2 Protein hemic and lymphatic diseases Tumor Cells Cultured Humans Immunoprecipitation Lymphoma Large-Cell Anaplastic Tyrosine Microsatellite Instability Lymphoma Large B-Cell Diffuse Phosphorylation Protein Multimerization DNA Damage |
| Zdroj: | The American journal of pathology. 179(1) |
| ISSN: | 1525-2191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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