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 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: Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, Nagasaki 852-8523, Japan.
authors: Koji
authors: K
authors: Ando
authors: Hideki
authors: H
authors: Tsushima
authors: Emi
authors: E
authors: Matsuo
authors: Kensuke
authors: K
authors: Horio
authors: Shinya
authors: S
authors: Tominaga-Sato
authors: Daisuke
authors: D
authors: Imanishi
authors: Yoshitaka
authors: Y
authors: Imaizumi
authors: Masako
authors: M
authors: Iwanaga
authors: Hidehiro
authors: H
authors: Itonaga
authors: Shinichiro
authors: S
authors: Yoshida
authors: Tomoko
authors: T
authors: Hata
authors: Ryozo
authors: R
authors: Moriuchi
authors: Hitoshi
authors: H
authors: Kiyoi
authors: Stephen
authors: S
authors: Nimer
authors: Hiroyuki
authors: H
authors: Mano
authors: Tomoki
authors: T
authors: Naoe
authors: Masao
authors: M
authors: Tomonaga
authors: Yasushi
authors: Y
authors: Miyazaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D010750:Phosphoproteins / Q000737:chemistry*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D020298:U937 Cells
chemical_list: D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000090243:Nucleophosmin; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase
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