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Molecular and Cellular Biology, October 2001, p. 6859-6869, Vol. 21, No. 20
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 (
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

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