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J. Biol. Chem., Vol. 280, Issue 14, 13364-13373, April 8, 2005

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Differential STAT5 Signaling by Ligand-dependent and Constitutively Active Cytokine Receptors^*

Virginie Moucadel and Stefan N. Constantinescu

From the Ludwig Institute for Cancer Research, Brussels B-1200, Belgium and the Christian de Duve Institute of Cellular Pathology & MEXP Unit, Université de Louvain, Brussels B-1200, Belgium

Many leukemia and cancer cells exhibit constitutive activation of STAT5, which was suggested to provide an anti-apoptotic advantage. Transformation of cytokine-dependent hematopoietic cells, such as Ba/F3 cells to autonomous growth and tumorigenicity equally results in selection for constitutive activation of STAT5. We compared STAT5 signaling between erythropoietin(Epo)-dependent cells and cells that were transformed by oncogenic activation of the erythropoietin receptor (EpoR) by coexpression of the gp55-P envelope protein of the spleen focus forming virus or by expression of the R129C constitutively active EpoR mutant. In transformed cells it was mainly STAT5B that was constitutively activated. In contrast, Epo stimulation activated both STAT5A and STAT5B. In transformed cells, chromatin immunoprecipitation (ChIP) showed STAT5 to be physically bound to promoters of STAT5 target genes, such as Bcl_XL, and to be able to promote transactivation of the Bcl_XL promoter in a constitutive fashion. Sequencing of native sequences after ChIP with anti-STAT5 antibodies in Epo-dependent and -transformed cells indicated that in gp55-transformed cells, STAT5B bound in the chromatin not only to N3 high affinity, but also to low affinity N4 GAS sites. Transactivation for N3 GAS sites in luciferase reporters was specific to gp55 transformation. Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.

Received for publication, June 30, 2004 , and in revised form, January 20, 2005.

^* This work was supported by grants from the Fédération Belge contre le Cancer, from the Fonds National de la Recherche Scientifique (F. N. R. S.), and from the de Hovre Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Data.

Supported by a Marie Curie Fellowship and by a Delori Fellowship of the Christian de Duve Institute of Cellular Pathology.

A Research Associate of the F. N. R. S. Belgium To whom correspondence should be addressed: Ludwig Institute for Cancer Research, Brussels B-1200, Belgium. Tel.: 32-2-764-7540; Fax: 32-2-764-6566; E-mail: stefan.constantinescu{at}bru.licr.org.

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