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Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

Oncogene volume 23, pages 4389–4399 (2004)Cite this article

Abstract

The hematopoietic transcription factor Spi-1/PU.1 is an oncoprotein participating to the malignant transformation of proerythroblasts in the Friend erythroleukemia or in the erythroleukemic process developed in spi-1 transgenic mice. Overexpression of Spi-1 in proerythroblasts blocks their differentiation. We have shown that Spi-1 promotes the use of the proximal 5′-splice site during the E1A pre-mRNA splicing and interferes with the effect of TLS (Translocated in LipoSarcoma) in this splicing assay. TLS was identified from chromosomal translocations in human liposarcoma and acute myeloid leukemia. Here, we determine the function of Spi-1 domains in splicing and in the interference with TLS. In transient transfection assays in erythroid cells, we show that the DNA binding domain cooperates with the transactivation domain or the PEST region of Spi-1 to modify the function of TLS in splicing. Interestingly, the 27 C-terminal amino acids, which determine the DNA binding activity of Spi-1, are necessary for the splicing function of Spi-1 as well as for its ability to interfere with TLS. Finally, we demonstrate that in leukemic proerythroblasts overexpressing Spi-1, TLS has lost its splicing effect. Thus, we hypothesize that oncogenic pathways in proerythroblasts may involve the ability of Spi-1 to alter splicing.

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Acknowledgements

We thank Jean de Gunzburg, Jacques Camonis, Olivier Kosmider and Erwan Le Scolan for their advice and comments regarding the manuscript. We are grateful to N Brandon for technical assistance. LD was supported by fellowships from the Société Française d’Hématologie and from the Association pour la Recherche contre le Cancer. This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale (Inserm), the Ligue Nationale contre le Cancer, the Association pour la Recherche contre le Cancer and the Fondation pour la Recherche Médicale.

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  1. Laurent Delva

    Present address: Inserm EMI 00-03, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France

  2. Laurent Delva and Isabelle Gallais: The first two authors contribute equally to this work

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  1. Inserm U528, Section de recherche, Institut Curie, Paris, France

    Laurent Delva, Isabelle Gallais, Christel Guillouf, Nicole Denis, Christophe Orvain & Francoise Moreau-Gachelin

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Correspondence to Francoise Moreau-Gachelin.

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Delva, L., Gallais, I., Guillouf, C. et al. Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells. Oncogene 23, 4389–4399 (2004). https://doi.org/10.1038/sj.onc.1207578

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