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Originally published In Press as doi:10.1074/jbc.M010692200 on March 26, 2001

J. Biol. Chem., Vol. 276, Issue 23, 20108-20115, June 8, 2001
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PEA3 Is Up-regulated in Response to Wnt1 and Activates the Expression of Cyclooxygenase-2*

Louise R. HoweDagger §, Howard C. Crawford||**, Kotha Subbaramaiah§Dagger Dagger , John A. Hassell§§¶¶, Andrew J. Dannenberg§Dagger Dagger , and Anthony M. C. BrownDagger §

From the Dagger  Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, New York, New York 10021, the § Strang Cancer Research Laboratory at the Rockefeller University, New York, New York 10021, the || Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the Dagger Dagger  Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, and the §§ Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario L86 4K1, Canada

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is aberrantly expressed in intestinal tumors resulting from APC mutation, and is also transcriptionally up-regulated in mouse mammary epithelial cells in response to Wnt1 expression. beta -Catenin stabilization is a consequence of both APC mutation and Wnt signaling. We have previously observed coordinate regulation of the matrilysin promoter by beta -catenin and Ets family transcription factors of the PEA3 subfamily. Here we show that while beta -catenin only weakly activates the COX-2 promoter, PEA3 family transcription factors are potent activators of COX-2 transcription. Consistent with this, PEA3 is up-regulated in Wnt1-expressing mouse mammary epithelial cells, and PEA3 factors are highly expressed in tumors from Wnt1 transgenic mice, in which Cox-2 is also up-regulated. Promoter mapping experiments suggest that the NF-IL6 site in the COX-2 promoter is important for mediating PEA3 responsiveness. The NF-IL6 site is also important for COX-2 transcription in some colorectal cancer lines (Shao, J., Sheng, H., Inoue, H., Morrow, J. D., and DuBois, R. N. (2000) J. Biol. Chem. 275, 33951-33956), and PEA3 factors are highly expressed in colorectal cancer cell lines. Therefore, we speculate that PEA3 factors may contribute to the up-regulation of COX-2 expression resulting from both APC mutation and Wnt1 expression.

* This work was supported in part by National Institutes of Health Grants CA47207 (to A. M. C. B.) and CA89578 (to A. J. D.), United States Department of the Army Grant DAMD17-98-1-8057 (to A. J. D.), and a grant from the Irving Weinstein Foundation (to L. R. H.).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: Strang Cancer Research Laboratory, Rockefeller University, Box 231, 1230 York Ave., New York, NY 10021. Tel.: 212-734-0567; Fax: 212-472-9471; E-mail: lrhowe@med.cornell.edu.

** Supported by American Cancer Society Pilot Project Grant IRG-58-009-41.

¶¶ Supported by the Canadian Institutes of Health Research and the Canadian Breast Cancer Research Initiative.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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