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Volume 272, Number 42, Issue of October 17, 1997 pp. 26620-26626
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Clusterin Gene Expression by Transforming Growth Factor

(Received for publication, March 27, 1997, and in revised form, August 4, 1997)

From the Department of Cell Biology (NC-1), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106

Transforming growth factor  (TGF) induces the expression of a wide variety of genes in many cell types. Our previous studies have shown that TGF stimulates both clusterin mRNA and protein levels, and induces its accumulation in the nucleus of CCL64 cells. To further investigate the molecular mechanism of clusterin mRNA induction by TGF, we created a 1.3-kilobase rat clusterin promoter/luciferase reporter construct. We demonstrate that TGF enhances luciferase activity 2.5-6-fold in transient transfection assays of epithelial, endothelial, and fibroblast cell lines. Deletional analysis reveals that an AP-1-binding site (5-TGAGTCA) in the minimal promoter region is necessary for initiating transactivation by TGF. A single T to G base mutation in the AP-1 site (5-TGAGGCA) abolishes TGF-induced clusterin promoter transactivation. In transcription factor decoy experiments, 23-mer oligonucleotides of wild type AP-1 reduce TGF induction of clusterin mRNA levels and promoter transactivation, while an oligonucleotide containing the mutated AP-1 site has no effect. Two specific protein kinase C inhibitors, GF109203X and calphostin C, block TGF-induced clusterin mRNA levels and promoter transactivation. Together these results indicate that TGF regulates clusterin gene expression through an AP-1 site and its cognate transcription factor AP-1, and requires the involvement of protein kinase C.

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