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J. Biol. Chem., Vol. 279, Issue 26, 27764-27773, June 25, 2004

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Smad3 Interacts with JunB and Cbfa1/Runx2 for Transforming Growth Factor-1-stimulated Collagenase-3 Expression in Human Breast Cancer Cells^*

Nagarajan Selvamurugan, Sukyee Kwok, and Nicola C. Partridge

From the Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

We have previously shown that transforming growth factor (TGF)-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 runt domain (RD) and proximal RD/activator protein-1 (AP-1) sites as necessary for full TGF-1-stimulated collagenase-3 promoter activity. Gel shift, real time reverse transcriptase-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 the 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 that Smad3 is likely to stabilize their interaction to confer functional TGF-1-stimulation of collagenase-3 expression in MDA-MB231 cells.

Received for publication, November 25, 2003 , and in revised form, April 13, 2004.

^* This work was supported by Department of Defense Grant DAMD17-01-1-0656, the New Jersey Commission on Cancer Research and the Foundation of University of Medicine and Dentistry of New Jersey (to N. S.), and National Institutes of Health Grant DK47420 (to N. C. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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 Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-2821; Fax: 732-235-5038; E-mail: selvamn2{at}umdnj.edu.

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