Abstract
Activation of Stat5 by many cytokines implies that it cannot alone insure the specificity of the regulation of its target genes. We have evidenced a physical and functional interaction between members of two unrelated transcription factor families, Ets-1, Ets-2 and Stat5, which could contribute to the proliferative response to interleukin 2. Competition with GAS- and EBS-specific oligonucleotides and immunoassays with a set of anti-Stat and anti-Ets families revealed that the IL-2-induced Stat5-Ets complex recognizes several GAS motifs identified as target sites for activated Stat5 dimers. Coimmunoprecipitation experiments evidenced that a Stat5/Ets-1/2 complex is formed in vivo in absence of DNA. GST-pull down experiments demonstrated that the C-terminal domain of Ets-1 is sufficient for this interaction in vitro. Cotransfection experiments in Kit225 T cells resulted in cooperative transcriptional activity between both transcription factors in response to a combination of IL-2, PMA and ionomycin. A Stat5-Ets protein complex was the major inducible DNA-binding complex bound to the human IL-2rE GASd/EBSd motif in long-term proliferating normal human T cells activated by CD2 and CD28. These results suggest that the inducible Stat5-Ets protein interaction plays a role in the regulation of gene expression in response to IL-2 in human T lymphocytes.
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Acknowledgements
We thank C Lipcey for excellent technical assistance, Dr P Benech and C Mawas for critical reading of the manuscript. Dr FC De la Brousse, B Groner, SL McKnight and M Sieweke generously provided specific antisera and constructs. This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants from Association pour la Recherche sur le Cancer, Comité des Bouches-du-Rhône de la Ligue Nationale Contre le Cancer and the European Community Grant CHRX CT 94-0537. It partially fulfils the requirement for the doctoral thesis of P Rameil. P Lecine and P Rameil were supported by fellowships from the Ministère de l'Enseignement Supérieur et de la Recherche and from the Association pour la Recherche sur le Cancer.
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Rameil, P., Lécine, P., Ghysdael, J. et al. IL-2 and long-term T cell activation induce physical and functional interaction between STAT5 and ETS transcription factors in human T cells. Oncogene 19, 2086–2097 (2000). https://doi.org/10.1038/sj.onc.1203542
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DOI: https://doi.org/10.1038/sj.onc.1203542
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