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Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells

Oncogene volume 23, pages 920–927 (2004)Cite this article

Abstract

The inclusion of exon 16 in mature protein 4.1R mRNA arises from a stage-specific splicing event that occurs during late erythroid development. We have shown that mouse erythroleukemia (MEL) cells reproduce this erythroid-specific splicing event upon induction of differentiation. We here found that this splicing event is regulated specifically in erythroleukemic cells that have the potential to differentiate and produce hemoglobin, regardless of the nature of the differentiation inducer. Knowing that dysregulated expression of spi-1/pu.1 and fli-1 oncogenes is involved in MEL cell differentiation arrest, we looked at their effect on exon 16 erythroid splicing. We found that exon 16 inclusion requires Spi-1/PU.1 shutdown in MEL cells, and that enforced expression of Spi-1/PU.1 inhibits exon selection, regardless of the presence or absence of a chemical inducer. By contrast, endogenous overexpression or enforced expression of Fli-1 has no effect on exon selection. We further showed that Spi-1/PU.1 acts similarly on the endogenous and on a transfected exon 16, suggesting a promoter-independent effect of Spi-1/PU.1 on splicing regulation. This study provides the first evidence that Spi-1/PU.1 displays the unique property, not shared with Fli-1, to inhibit erythroid-specific pre-mRNA splicing in erythroleukemia cell context.

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Abbreviations

DMSO:

dimethylsulfoxide

EMSA:

electrophoretic mobility shift assay

Epo:

erythropoietin

F-MuLV:

Friend murine leukemia virus

GST:

glutathione-S-transferase

HMBA:

hexamethylene-bisacetamide

MEL:

mouse erythroleukemia

SAB:

spectrin/actin-binding

SFFV:

spleen focus-forming virus

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Acknowledgements

We are most grateful to Drs EJ Benz Jr, SC Huang, Y Ikawa, I Katoh and R Supino, for providing MEL cell clones, and Drs M Hanspal and A Sytkowski for Rauscher cells. This work was supported by the ‘Ligue Nationale Contre le Cancer’, the ‘Ligue Contre le Cancer, Comité de la Loire’, the ‘Association pour la Recherche sur le Cancer’, the ‘Centre National de la Recherche Scientifique’ and the ‘Institut National de la Santé et de la Recherche Médicale’.

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Authors and Affiliations

  1. Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Lyon 1, Villeurbanne, France

    Orianne Théoleyre, Mireille Deguillien, Madeleine Morinière, Joëlle Starck, François Morlé & Faouzi Baklouti

  2. Laboratoire de Transduction du Signal et Oncogenèse, Inserm U528, Institut Curie, Paris, France

    Françoise Moreau-Gachelin

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  1. Orianne Théoleyre
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Correspondence to Faouzi Baklouti.

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Théoleyre, O., Deguillien, M., Morinière, M. et al. Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells. Oncogene 23, 920–927 (2004). https://doi.org/10.1038/sj.onc.1207206

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