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Papers In Press, published online ahead of print April 14, 2004
Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854
Corresponding Author: selvamn2{at}umdnj.edu
We have previously shown that TGF (transforming growth factor)-
J. Biol. Chem, 10.1074/jbc.M312870200
Submitted on November 25, 2003
Revised on April 14, 2004
Accepted on April 14, 2004
Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-
1-stimulated collagenase-3 expression in human breast cancer cells
1, a crucial molecule in metastatic bone cancer, stimulates collagenase-3 expression in the human breast cancer cell line, MDA-MB231. To understand the molecular mechanisms responsible for TGF-1-response on collagenase-3 promoter activity, a functional analysis of the promoter region of the collagenase-3 gene was carried out and we identified the distal RD (runt domain) and proximal RD/AP-1 (activator protein-1) sites as necessary for full TGF-1-stimulated collagenase-3 promoter activity. Gel shift, real time RT-PCR and Western blot analyses showed increased levels of c-Jun, JunB, and Cbfa1/Runx2 upon TGF-1 treatment in MDA-MB231 cells. Co-immunoprecipitation in vitro studies identified no physical interaction between JunB and Cbfa1/Runx2; whereas Smad3 interacted with both. Chromatin immunoprecipitation experiments confirmed interaction of Smad3 with JunB and Cbfa1/Runx2. Under basal conditions, Cbfa1/Runx2 bound to both the proximal RD/AP-1 and distal RD sites. In response to TGF-1, Cbfa1/Runx2 was seen only at the distal RD site; whereas JunB occupied the proximal RD/AP-1 site. An assemblage of Smad3, JunB, and Cbfa1/Runx2 at the distal RD site of the collagenase-3 promoter occurred in response to TGF-1 in MDA-MB231 cells. Co-transfection of Smad3, JunB, and Cbfa1/Runx2 constructs along with a constitutively active TGF- type I receptor construct identified functional interaction of these proteins and transcriptional activation of collagenase-3 gene by TGF-1. Taken together, our results suggest that TGF-1 stimulated JunB and Cbfa1/Runx2 to bind to their respective DNA consensus sites and Smad3 is likely to stabilize their interaction to confer functional TGF-1-stimulation of collagenase-3 expression in MDA-MB231 cells.
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