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Molecular and Cellular Biology, October 2001, p. 6859-6869, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6859-6869.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Differential Interactions of Specific Nuclear Factor I Isoforms with the Glucocorticoid Receptor and STAT5 in the Cooperative Regulation of WAP Gene Transcription

Sudit S. Mukhopadhyay,1 Shannon L. Wyszomierski,1,dagger Richard M. Gronostajski,2 and Jeffrey M. Rosen1,*

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030,1 and Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 20 April 2001/Returned for modification 26 June 2001/Accepted 11 July 2001

The distal region (-830 to -720 bp) of the rat whey acidic protein (WAP) gene contains a composite response element (CoRE), which has been demonstrated previously to confer mammary gland-specific and hormonally regulated WAP gene expression. Point mutations in the binding sites for specific transcription factors present within this CoRE have demonstrated the importance of both nuclear factor I (NFI) and STAT5 as well as cooperative interactions with the glucocorticoid receptor (GR) in the regulation of WAP gene expression in the mammary gland of transgenic mice. This study reports the characterization of NFI gene expression during mammary gland development and the identification and cloning of specific NFI isoforms (NFI-A4, NFI-B2, and NFI-X1) from the mouse mammary gland during lactation. Some but not all of these NFI isoforms synergistically activate WAP gene transcription in cooperation with GR and STAT5, as determined using transient cotransfection assays in JEG-3 cells. On both the WAP CoRE and the mouse mammary tumor virus long terminal repeat promoter, the NFI-B isoform preferentially activated gene transcription in cooperation with STAT5A and GR. In contrast, the NFI-A isoform suppressed GR and STAT cooperativity at the WAP CoRE. Finally, unlike their interaction with the NFI consensus binding site in the adenovirus promoter, the DNA-binding specificities of the three NFI isoforms to the palindromic NFI site in the WAP CoRE were not identical, which may partially explain the failure of the NFI-A isoform to cooperate with GR and STAT5A.

* Corresponding author. Mailing address: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-6210. Fax: (713) 798-8012. E-mail: jrosen{at}bcm.tmc.edu.

dagger Present address: Department of Biochemistry, M. D. Anderson Cancer Center, Houston, TX 77030.

Molecular and Cellular Biology, October 2001, p. 6859-6869, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6859-6869.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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