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Molecular and Cellular Biology, June 1999, p. 3940-3950, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Dimeric RFX Proteins Contribute to the Activity and Lineage Specificity of the Interleukin-5 Receptor alpha  Promoter through Activation and Repression Domains

Atsushi Iwama,1,2 Jing Pan,1 Pu Zhang,1 Walter Reith,3 Bernard Mach,3 Daniel G. Tenen,1 and Zijie Sun1,4,*

Hematology/Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 022151; Louis Jeantet Laboratory of Molecular Genetics, Departments of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland3; Liem Sioe Liong Molecular Biology Laboratory, Department of Surgery and Genetics, Stanford University School of Medicine, Stanford, California 94305-53284; and Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto, Japan2

Received 9 October 1998/Returned for modification 25 November 1998/Accepted 3 March 1999

Interleukin-5 (IL-5) plays a central role in the differentiation, proliferation, and functional activation of eosinophils. The specific action of IL-5 on eosinophils and hematopoietically related basophils is regulated by the restricted expression of IL-5 receptor alpha  (IL-5Ralpha ), a subunit of high-affinity IL-5R, on these cells. We have previously identified an enhancer-like cis element in the IL-5Ralpha promoter that is important for both full promoter function and lineage-specific activity. Here, we demonstrate by yeast one-hybrid screening that RFX2 protein specifically binds to this cis element. RFX2 belongs to the RFX DNA-binding protein family, the biological role of which remains obscure. Using an electrophoretic mobility shift assay, we further show that RFX1, RFX2, and RFX3 homodimers and heterodimers specifically bind to the cis element of the IL-5Ralpha promoter. The mRNA expression of RFX1, RFX2, and RFX3 was detected ubiquitously, but in transient-transfection assays, multimerized RFX binding sites in front of a basal promoter efficiently functioned in a tissue- and lineage-specific manner. To further investigate RFX functions on transcription, full-length and deletion mutants of RFX1 were targeted to DNA through fusion to the GAL4 DNA binding domain. Tissue- and lineage-specific transcriptional activation with the full-length RFX1 fusion plasmid on a reporter controlled by GAL4 binding sites was observed. Distinct activation and repression domains within the RFX1 protein were further mapped. Our findings suggest that RFX proteins are transcription factors that contribute to the activity and lineage specificity of the IL-5Ralpha promoter by directly binding to a target cis element and cooperating with other tissue- and lineage-specific cofactors.

* Corresponding author. Mailing address: Department of Surgery and Genetics, R135, Edwards Building, Stanford University School of Medicine, Stanford, CA 94305-5328. Phone: (650) 498-7523. Fax: (650) 725-8502. E-mail: zsun{at}leland.stanford.edu.

Molecular and Cellular Biology, June 1999, p. 3940-3950, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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