Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation

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 D Nimer, Hiroyuki Mano, Tomoki Naoe, Masao Tomonaga, Yasushi Miyazaki

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9457-9467
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number13
DOIs
StatePublished - Mar 29 2013
Externally publishedYes

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Phosphoproteins
Leukemia
Transcription Factors
Mutation
Mutant Proteins
Purification
Assays
Genes
Oncogenes
Messenger RNA
DNA
Neoplasms
Proteins
Experiments
nucleophosmin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation. / Ando, Koji; Tsushima, Hideki; Matsuo, Emi; Horio, Kensuke; Tominaga-Sato, Shinya; Imanishi, Daisuke; Imaizumi, Yoshitaka; Iwanaga, Masako; Itonaga, Hidehiro; Yoshida, Shinichiro; Hata, Tomoko; Moriuchi, Ryozo; Kiyoi, Hitoshi; Nimer, Stephen D; Mano, Hiroyuki; Naoe, Tomoki; Tomonaga, Masao; Miyazaki, Yasushi.

In: Journal of Biological Chemistry, Vol. 288, No. 13, 29.03.2013, p. 9457-9467.

Research output: Contribution to journalArticle

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, SD, Mano, H, Naoe, T, Tomonaga, M & Miyazaki, Y 2013, 'Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation', Journal of Biological Chemistry, vol. 288, no. 13, pp. 9457-9467. https://doi.org/10.1074/jbc.M112.415703
Ando, Koji ; Tsushima, Hideki ; Matsuo, Emi ; Horio, Kensuke ; Tominaga-Sato, Shinya ; Imanishi, Daisuke ; Imaizumi, Yoshitaka ; Iwanaga, Masako ; Itonaga, Hidehiro ; Yoshida, Shinichiro ; Hata, Tomoko ; Moriuchi, Ryozo ; Kiyoi, Hitoshi ; Nimer, Stephen D ; Mano, Hiroyuki ; Naoe, Tomoki ; Tomonaga, Masao ; Miyazaki, Yasushi. / Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 13. pp. 9457-9467.
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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.",
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AU - Ando, Koji

AU - Tsushima, Hideki

AU - Matsuo, Emi

AU - Horio, Kensuke

AU - Tominaga-Sato, Shinya

AU - Imanishi, Daisuke

AU - Imaizumi, Yoshitaka

AU - Iwanaga, Masako

AU - Itonaga, Hidehiro

AU - Yoshida, Shinichiro

AU - Hata, Tomoko

AU - Moriuchi, Ryozo

AU - Kiyoi, Hitoshi

AU - Nimer, Stephen D

AU - Mano, Hiroyuki

AU - Naoe, Tomoki

AU - Tomonaga, Masao

AU - Miyazaki, Yasushi

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N2 - 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.

AB - 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.

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