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Molecular and Cellular Biology, May 2009, p. 2852-2864, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01435-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Spi-1 and Fli-1 Directly Activate Common Target Genes Involved in Ribosome Biogenesis in Friend Erythroleukemic Cells{triangledown} ,{dagger}

Gaëtan Juban,1,§ Guillaume Giraud,1,§ Boris Guyot,1 Stéphane Belin,1 Jean-Jacques Diaz,1 Joëlle Starck,1 Christel Guillouf,2 Françoise Moreau-Gachelin,2 and François Morlé1*

Université de Lyon, Lyon F-69003, Université Lyon 1, Lyon F-69003, and CNRS, UMR5534, Centre de Génétique Moléculaire et Cellulaire, Villeurbanne F-69622, France,1 INSERM U830, Section de Recherche, Institut Curie, 26 rue d'Ulm, Paris F-75248, France2

Received 11 September 2008/ Returned for modification 1 November 2008/ Accepted 3 March 2009

Spi-1 and Fli-1 are ETS transcription factors recurrently deregulated in mouse erythroleukemia induced by Friend viruses. Since they share the same core DNA binding site, we investigated whether they may contribute to erythroleukemia by common mechanisms. Using inducible knockdown, we demonstrated that Fli-1 contributes to proliferation, survival, and differentiation arrest of erythroleukemic cells harboring an activated fli-1 locus. Similarly, we used inducible Fli-1 knockdown and either hexamethylenebisacetamide (HMBA)- or small interfering RNA-mediated Spi-1 knockdown to investigate their respective contributions in erythroleukemic cells harboring an activated spi-1 locus. In these cells, simple or double knockdown of both Spi-1 and Fli-1 additively contributed to induce proliferation arrest and differentiation. Transcriptome profiling revealed that virtually all transcripts affected by both Fli-1 knockdown and HMBA are affected in an additive manner. Among these additively downregulated transcripts, more than 20% encode proteins involved in ribosome biogenesis, and conserved ETS binding sites are present in their gene promoters. Through chromatin immunoprecipitation, we demonstrated the association of Spi-1 and Fli-1 on these promoters in Friend erythroleukemic cells. These data lead us to propose that the oncogenicity of Spi-1, Fli-1, and possibly other ETS transcription factors may involve their ability to stimulate ribosome biogenesis.

* Corresponding author. Mailing address: Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Lyon 1, 16 rue Dubois, 69 622 Villeurbanne, France. Phone: 33 (0)4 72 43 36 37. Fax: 33 (0)4 72 43 26 85. E-mail: morle{at}univ-lyon1.fr

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

§ Contributed equally to this work.

Molecular and Cellular Biology, May 2009, p. 2852-2864, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01435-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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