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© The Rockefeller University Press, 0022-1007/1997/4/1211/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1211-1222

Article

Elf-1 Contributes to the Function of the Complex Interleukin (IL)-2–responsive Enhancer in the Mouse IL-2 Receptor {alpha} Gene

Irina Serdobova*, Maria Pla*, Patrick Reichenbach*, Peter Sperisen*, Jacques Ghysdael{ddagger}, Anne Wilson§, Jonathan Freeman||, and Markus Nabholz*

From the * Lymphocyte Biology Unit, Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges, Switzerland; {ddagger} Section de Biologie, Institut Curie, F-91405 Orsay Cédex, France; § Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland; and || Génétique et Microbiologie, Centre Médical Universitaire, Universite de Genève, 1211 Genève 4, Switzerland

Lymphocytes regulate their responsiveness to IL-2 through the transcriptional control of the IL-2R{alpha} gene, which encodes a component of the high affinity IL-2 receptor. In the mouse IL-2R{alpha} gene this control is exerted via two regulatable elements, a promoter proximal region, and an IL-2–responsive enhancer (IL-2rE) 1.3 kb upstream. In vitro and in vivo functional analysis of the IL-2rE in the rodent thymic lymphoma-derived, CD4–CD8– cell line PC60 demonstrated that three separate elements, sites I, II, and III, were necessary for IL-2 responsiveness; these three sites demonstrate functional cooperation. Site III contains a consensus binding motif for members of the Ets family of transcription factors. Here we demonstrate that Elf-1, an Ets-like protein, binds to site III and participates in IL-2 responsiveness. In vitro site III forms a complex with a protein constitutively present in nuclear extracts from PC60 cells as well as from normal CD4–CD8– thymocytes. We have identified this molecule as Elf-1 according to a number of criteria. The complex possesses an identical electrophoretic mobility to that formed by recombinant Elf-1 protein and is super-shifted by anti–Elf-1 antibodies. Biotinylated IL-2rE probes precipitate Elf-1 from PC60 extracts provided site III is intact and both recombinant and PC60-derived proteins bind with the same relative affinities to different mutants of site III. In addition, by introducing mutations into the core of the site III Ets-like motif and comparing the corresponding effects on the in vitro binding of Elf-1 and the in vivo IL-2rE activity, we provide strong evidence that Elf-1 is directly involved in IL-2 responsiveness. The nature of the functional cooperativity observed between Elf-1 and the factors binding sites I and II remains unresolved; experiments presented here however suggest that this effect may not require direct interactions between the proteins binding these three elements.

Address correspondence to Markus Nabholz, Lymphocyte Biology Unit, Swiss Institute for Experimental Cancer Research, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Dr. Pla's current address is Department Biologia Cellular, Universitat de Girona, Pl. Hospital 6, 171071 Girona, Spain. Dr. Serdobova's current address is Départment de Biologie Moléculaire, Universite de Genève, 1211 Genève 4, Switzerland.

This work was supported, in part, by grants from the Swiss National Science Foundation and the Swiss Cancer League, to M.N, as well as by grants from the Swiss Federal Office of Education and Science awarded in conjunction with projects approved by the Biomed and Human Capital and Mobility programs of the European Union.

1 Abbreviations used in this paper: IL-2R, IL-2 receptor; IL-2rE, IL-2–responsive enhancer; PRR, promoter-proximal positive regulatory region; STAT, signal transducers and activators of transcription.


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