Nucleic Acids Research, 1991, Vol. 19, No. 23 6419-6425
© 1991
MOLECULAR BIOLOGY |
Sequence specific protein binding to and activation of the TGF-ß3 promoter through a repeated TCCC motif
Laboratory of Chemoprevention, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA 1Department of Biochemistry, University of California at Berkeley Berkeley, CA, USA
*To whom correspondence should be addressed at Centre d'Immunologie et de Biologie Parasitaire, Unite mixte INSERM U167-CNRS U624 Institut Pasteur, BP 245, I, rue du P. Calmette, 59000 Lille cedex, France
Received September 27, 1991. Accepted November 8, 1991.
We have previously characterized the TGF-ß3 promoter and shown that the activity of this promoter is highly variable in different cell types. Although the promoter contains a proximal cAMP responsive element, which is critical to basal and forskolin-induced promoter activity, this element is not responsible for the variable, cell-specific regulation of the promoter. In this paper, we identify a 25 base pair sequence in the proximal region of the TGF-ß3 promoter that binds a novel DNAbinding protein. This region includes the sequence TCCCTCCCTCCC, (3 x TCCC), and mutation of these TCCC repeats inhibits protein binding. Further, we show that in the cell line A375, which we have previously shown expresses high levels of TGF-ß3 mRNA, this region is responsible for mediating high level TGF-ß3 promoter activity. Immediately 3' to the 3 x TCCC sequence is a consensus AP-2 binding site, however, we show that this region does not bind AP-2, and AP-2 does not transactivate the TGF-ß3 promoter. Therefore, we provide strong evidence that high level expression of TGF-ß3 in A375 cells results from transactivation of the TGF-ß3 promoter by a protein that binds to a repeated TCCC motif in the promoter and suggest that this ONA-binding protein likely also regulates aspects of developmental and tissue-specific expression of this cytokine
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