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J Biol Chem, Vol. 275, Issue 16, 12231-12236, April 21, 2000
From the Progression of MCF-7 cells from early passage
(MCF-7E, <200 passage) to late passage (MCF-7L, >500 passage)
correlates with a loss of sensitivity to exogenous TGF
The Role of Sp1 in the Differential Expression of Transforming
Growth Factor-
Receptor Type II in Human Breast Adenocarcinoma MCF-7
Cells*
§,,
Department of Biochemistry and Molecular
Biology, Medical College of Ohio, Toledo, Ohio 43614-5804 and the
¶ Department of Surgery, University of Texas Health Science
Center, San Antonio, Texas 78284-7840
1. We have
previously shown that loss of TGF sensitivity is due to decreased
expression of the transforming growth factor receptor type II (TRII)
and is associated with increased tumorigenicity in nude mice. Reduced TRII expression in MCF-7L cells is caused by decreased TRII promoter activity in this cell line. Our previous studies using 5'
deletion constructs of this promoter revealed that MCF-7L cells were
unable to support transcription of the minimal promoter (
47 to +2) to
the same levels as the MCF-7E cells. This region of the promoter
contains an Sp1 element at position 25 from the major transcription
start site. In this study, we investigated the role of Sp1 in TRII
transcription. Mutation of the Sp1 site resulted in decreased
transcription of TRII in MCF-7E and MCF-7L cells, indicating that
this site played a role in transcription of this promoter. Gel shift
assays using the proximal Sp1 site from the TRII promoter showed
enhanced DNA:protein complex formation with nuclear proteins isolated
from MCF-7E cells compared with MCF-7L cells. Supershift analysis
identified this binding activity as Sp1. Western blot analysis of Sp1
levels demonstrated that MCF-7E cells contain increased Sp1 protein
compared with MCF-7L cells, paralleling the increased binding activity.
Differential Sp1 activity was also demonstrated by higher levels of
transcription of an Sp1-dependent insulin-like growth
factor II promoter construct in MCF-7E cells compared with MCF-7L
cells. Co-transfection of an Sp1 expression vector with a TRII
promoter construct in MCF-7L cells induced the expression from the
promoter-CAT constructs and resulted in an increase of endogenous
TRII protein levels. These results demonstrate that the
transcriptional repression of TRII in MCF-7L cells is caused, in
part, by lower Sp1 levels.
*
This work was supported by National Institutes of Health
Grants R29 CA79840 (to S. S. B.) and RO1 CA72001-01A1 (to
M. G. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Biochemistry and Molecular Biology, 3035 Arlington Ave., BHS 413, Medical College of Ohio, Toledo, OH 43614-5804. Tel.: 419-383-4137;
Fax: 419-383-6228; E-mail: sbanerji@mco.edu.
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