Synergistic Transcriptional Activation of the Tissue Inhibitor of Metalloproteinases-1 Promoter via Functional Interaction of AP-1 and Ets-1 Transcription Factors

doi:10.1074/jbc.271.2.774

Synergistic Transcriptional Activation of the Tissue Inhibitor of Metalloproteinases-1 Promoter via Functional Interaction of AP-1 and Ets-1 Transcription Factors (*)

From the (1)Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, California 94143, the
(2)Department of Microbiology and the Kaplan Cancer Center, New York University Medical Center, New York, New York 10016, and the
(3)Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195

^¶ To whom correspondence should be addressed:
Laboratory of Radiobiology and Environmental Health, Box 0750, University of California, San Francisco, CA 94143-0750.
Tel.: 415-476-4622; Fax: 415-476-0721; zena{at}radlab.ucsf.edu.

↵^§ Present address: Dept. of Pharmacology, New York University, School of Medicine, 550 First Ave., New York, NY 10016.

Abstract

The tissue inhibitor of metalloproteinases-1 (TIMP-1) is an inhibitor of the extracellular matrix-degrading metalloproteinases. We characterized response elements that control TIMP-1 gene expression. One contains a binding site that selectively binds c-Fos and c-Jun in vitro and confers a response to multiple AP-1 family members in vivo. Adjacent to this is a binding site for Ets domain proteins. Although c-Ets-1 alone did not activate transcription from this element, it enhanced transcription synergistically with AP-1 either in the context of the natural promoter or when the sequence was linked upstream of a heterologous promoter. Furthermore, a complex of c-Jun and c-Fos interacted with c-Ets-1 in vitro. These results suggest that AP-1 tethers c-Ets-1 to the TIMP-1 promoter via protein-protein interaction to achieve Ets-dependent transcriptional regulation. Collectively, our results indicate that TIMP-1 expression is controlled by several DNA response elements that respond to variations in the level and activity of AP-1 and Ets transcriptional regulatory proteins.

Footnotes

↵* This work was supported by Grants DE10306 and HD26732 from the National Institutes of Health, by the National Institutes of Health National Research Service Award 5 T32 ES07106 from the National Institute of Environmental Health Sciences, by Contract DE-AC03-76-SF01012 from the Office of Health and Environmental Research of the U. S. Department of Energy, and by senior fellowships from the Leukemia Foundation (to S. K. L. and M. J. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TIMP-1

tissue inhibitor of metalloproteinases-1

PBS

phosphate-buffered saline

CAT

chloramphenicol acetyltransferase

TRE

TPA response element

bp

base pair(s).
↵²S. K. Logan and Z. Werb, unpublished observations.
↵³R. S. Talhouk, M. J. Bissell, and Z. Werb, unpublished observations.
- Received July 10, 1995.
- Revision received October 4, 1995.