Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation Journal Article
| Authors: | Ando, K.; Tsushima, H.; Matsuo, E.; Horio, K.; Tominaga-Sato, S.; Imanishi, D.; Imaizumi, Y.; Iwanaga, M.; Itonaga, H.; Yoshida, S.; Hata, T.; Moriuchi, R.; Kiyoi, H.; Nimer, S.; Mano, H.; Naoe, T.; Tomonaga, M.; Miyazaki, Y. |
| Article Title: | Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation |
| Abstract: | Myeloid ELF1-like factor (MEF/ELF4), a member of the ETS transcription factors, can function as an oncogene in murine cancer models and is overexpressed in various human cancers. Here, we report a mechanism by which MEF/ELF4 may be activated by a common leukemia-associated mutation in the nucleophosmin gene. By using a tandem affinity purification assay, we found that MEF/ELF4 interacts with multifactorial protein nucleophosmin (NPM1). Coimmunoprecipitation and GST pull-down experiments demonstrated that MEF/ELF4 directly forms a complex with NPM1 and also identified the region of NPM1 that is responsible for this interaction. Functional analyses showed that wild-type NPM1 inhibited the DNA binding and transcriptional activity of MEF/ELF4 on theHDM2 promoter, whereas NPM1 mutant protein (Mt-NPM1) enhanced these activities of MEF/ELF4. Induction of Mt-NPM1 into MEF/ELF4-overexpressing NIH3T3 cells facilitated malignant transformation. In addition, clinical leukemia samples with NPM1 mutations had higher human MDM2 (HDM2) mRNA expression. Our data suggest that enhanced HDM2 expression induced by mutant NPM1 may have a role in MEF/ELF4-dependent leukemogenesis. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | adolescent; adult; clinical article; controlled study; protein expression; aged; middle aged; unclassified drug; acute granulocytic leukemia; gene mutation; human cell; promoter region; mutation; dna-binding proteins; mutant protein; binding affinity; protein function; protein localization; animals; mice; complex formation; gene overexpression; carboxy terminal sequence; protein protein interaction; protein binding; cell line, tumor; mutational analysis; wild type; transcription factors; nuclear proteins; oncogene; dna; transcription regulation; amino terminal sequence; messenger rna; rna, messenger; leukemogenesis; nucleic acids; glutathione transferase; immunoprecipitation; murinae; protein induction; phosphoproteins; binding site; inhibition kinetics; down regulation; upregulation; cell nucleus; mutant proteins; malignant transformation; cell strain 3t3; nih 3t3 cells; diseases; protein mdm2; transcription factor ets; proto-oncogene proteins c-mdm2; gene expression regulation, leukemic; u937 cells; transcriptional activity; nucleophosmin; hek293 cells; dna protein complex; myeloid elf1 like factor; mrna expression; activation analysis; tandem affinity purification; nucleophosmin gene; hdm2 gene; co-immunoprecipitations; ets transcription factor; malignant transformations; oncogenic transcription; myeloid elf1 like factor gene |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 288 |
| Issue: | 13 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2013-03-29 |
| Start Page: | 9457 |
| End Page: | 9467 |
| Language: | English |
| PROVIDER: | scopus |
| PMCID: | PMC3611015 |
| PUBMED: | 23393136 |
| DOI: | 10.1074/jbc.M112.415703 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2013" - "CODEN: JBCHA" - ":doi 10.1074/jbc.M112.415703" - "Source: Scopus" |
