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 the HDM2 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.

• Authors: Koji Ando, Hideki Tsushima, Emi Matsuo, Kensuke Horio, Shinya Tominaga-Sato, Daisuke Imanishi, Yoshitaka Imaizumi, Masako Iwanaga, Hidehiro Itonaga, Shinichiro Yoshida, Tomoko Hata, Ryozo Moriuchi, Hitoshi Kiyoi, Stephen Nimer, Hiroyuki Mano, Tomoki Naoe, Masao Tomonaga, Yasushi Miyazaki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 13 Pg. 9457-67 (Mar 29 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23393136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• ELF4 protein, human
• NPM1 protein, human
• Npm1 protein, mouse
• Nuclear Proteins
• Phosphoproteins
• RNA, Messenger
• Transcription Factors
• Nucleophosmin
• DNA
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Glutathione Transferase

Topics

• Adolescent
• Adult
• Aged
• Animals
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• DNA (metabolism)
• DNA-Binding Proteins (genetics)
• Female
• Gene Expression Regulation, Leukemic
• Glutathione Transferase (metabolism)
• HEK293 Cells
• Humans
• Male
• Mice
• Middle Aged
• Mutation
• NIH 3T3 Cells
• Nuclear Proteins (genetics, metabolism)
• Nucleophosmin
• Phosphoproteins (chemistry)
• Protein Binding
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• RNA, Messenger (metabolism)
• Transcription Factors (genetics)
• U937 Cells