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Molecular and Cellular Biology, October 1998, p. 5852-5860, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Sequence of the CIS Gene Promoter Interacts Preferentially with Two Associated STAT5A Dimers: a Distinct Biochemical Difference between STAT5A and STAT5B

Frédérique Verdier,1 Raquel Rabionet,1 Fabrice Gouilleux,1 Christian Beisenherz-Huss,2 Paule Varlet,1 Odile Muller,1 Patrick Mayeux,1 Catherine Lacombe,1 Sylvie Gisselbrecht,1 and Stany Chretien3,*

Institut Cochin de Génétique Moléculaire (ICGM), Institut National de la Santé et de la Recherche Médicale (INSERM U363), Hopital Cochin, Université René Descartes, F75014 Paris,1 and Institut National de la Transfusion Sanguine (INTS-GIP), F75015 Paris,3 France, and Tumor Biology Center, Institute for Experimental Cancer Research and Department of Biology, University of Freiburg, 79106 Freiburg, Germany2

Received 13 February 1998/Returned for modification 3 April 1998/Accepted 17 July 1998

Two distinct genes encode the closely related signal transducer and activator of transcription proteins STAT5A and STAT5B. The molecular mechanisms of gene regulation by STAT5 and, particularly, the requirement for both STAT5 isoforms are still undetermined. Only a few STAT5 target genes, among them the CIS (cytokine-inducible SH2-containing protein) gene, have been identified. We cloned the human CIS gene and studied the human CIS gene promoter. This promoter contains four STAT binding elements organized in two pairs. By electrophoretic mobility shift assay studies using nuclear extracts of UT7 cells stimulated with erythropoietin, we showed that these four sequences bound to STAT5-containing complexes that exhibited different patterns and affinities: the three upstream STAT binding sequences bound to two distinct STAT5-containing complexes (C0 and C1) and the downstream STAT box bound only to the slower-migrating C1 band. Using nuclear extracts from COS-7 cells transfected with expression vectors for the prolactin receptor, STAT5A, and/or STAT5B, we showed that the C1 complex was composed of a STAT5 tetramer and was dependent on the presence of STAT5A. STAT5B lacked this property and bound with a stronger affinity than did STAT5A to the four STAT sequences as a homodimer (C0 complex). This distinct biochemical difference between STAT5A and STAT5B was confirmed with purified activated STAT5 recombinant proteins. Moreover, we showed that the presence on the same side of the DNA helix of a second STAT sequence increased STAT5 binding and that only half of the palindromic STAT binding sequence was sufficient for the formation of a STAT5 tetramer. Again, STAT5A was essential for this cooperative tetrameric association. This property distinguishes STAT5A from STAT5B and could be essential to explain the transcriptional regulation diversity of STAT5.

* Corresponding author. Mailing address: Institut National de la Transfusion Sanguine (INTS-GIP), 6 rue Alexandre Cabanel, F75015 Paris, France. Phone: 33 1 46 33 14 09. Fax: 33 1 46 33 92 97. E-mail: chretien{at}cochin.inserm.fr.

Molecular and Cellular Biology, October 1998, p. 5852-5860, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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