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Molecular and Cellular Biology, January 1999, p. 121-135, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Spi-1/PU.1 Is a Positive Regulator of the Fli-1 Gene Involved in Inhibition of Erythroid Differentiation in Friend Erythroleukemic Cell Lines

Joëlle Starck,1 Alexandre Doubeikovski,2,dagger Sandrine Sarrazin,1 Colette Gonnet,1 Govinda Rao,3 Arthur Skoultchi,3 Jacqueline Godet,1 Isabelle Dusanter-Fourt,2 and François Morle1,*

Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, 69622 Villeurbanne,1 and INSERM U363, Institut Cochin de Génétique Moléculaire, Hôpital Cochin, 75014 Paris,2 France, and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 104613

Received 15 May 1998/Returned for modification 21 July 1998/Accepted 28 September 1998

Spi-1/PU.1 and Fli-1 are two members of the ETS family of transcription factors whose expression is deregulated by proviral insertion in most erythroleukemic cell lines induced by the spleen focus-forming virus (SFFV) and Friend murine leukemia virus (F-MuLV) components of the Friend viral complex, respectively. In this study, we present evidence that transcription of the Fli-1 gene is positively regulated by Spi-1/PU.1 in SFFV-transformed cell lines: (i) all SFFV-transformed cell lines expressing Spi-1/PU.1 are characterized by a specific pattern of Fli-1 gene transcripts initiated in the -200 region instead of position -400 as reported for F-MuLV-transformed cell lines; (ii) these Fli-1 transcripts initiated in the -200 region are downregulated in parallel with that of Spi-1/PU.1 during hexamethylenebisacetamide (HMBA) induced differentiation; and (iii) Fli-1 transcription is upregulated in SFFV cells lines following stable transfection of a Spi-1/PU.1 expression vector. Furthermore, we found by transient transfection assays that the -270/-41 region of the Fli-1 gene displays promoter activity which is transactivated by Spi-1/PU.1. This promoter is strictly dependent on the integrity of two highly conserved ETS DNA binding sites that bind the Spi-1/PU.1 protein in vitro. Finally, we show that transfection of constitutive or inducible Fli-1 expression vectors in SFFV-transformed cells inhibits their erythroid differentiation induced by HMBA. Overall, these data indicate that Fli-1 is a target gene of the Spi-1/PU.1 transcription factor in SFFV-transformed cell lines. We further suggest that deregulated synthesis of Fli-1 may trigger a common mechanism contributing to erythroleukemia induced by either SFFV or F-MuLV.

* Corresponding author. Mailing address: Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France. Phone: (33) 04 72 43 13 75. Fax: (33) 04 72 44 05 55. E-mail: morle{at}cismsun.univ-lyon1.fr.

dagger Present address: CNRS UPR 9051, Hôpital St. Louis, 75475 Paris, Cedex 10, France.

Molecular and Cellular Biology, January 1999, p. 121-135, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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