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J. Biol. Chem., Vol. 279, Issue 18, 18694-18700, April 30, 2004

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Polyoma Enhancer Activator 3, an Ets Transcription Factor, Mediates the Induction of Cyclooxygenase-2 by Nitric Oxide in Colorectal Cancer Cells^*

Yongmin Liu, Gregory L. Borchert, and James M. Phang¶

From the Metabolism & Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702 and the Basic Research Program, Science Applications International Corporation-Frederick, Inc., Maryland 21702

Abundant evidence supports the role of cyclooxygenase-2 (COX-2) in colorectal cancer. Nitric oxide (NO), a pro-inflammatory signaling factor, may regulate COX-2 expression and activity thereby linking hyper-inflammatory states to cancer susceptibility. Previously we showed that NO induced COX-2 expression. Although NO also activated the -catenin·T-cell factor/lymphocyte enhancing factor transcriptional pathway, a direct causal link between this pathway and COX-2 expression was not demonstrated. In this current study, we focused on NO-induced transcriptional activity and elucidated its role in COX-2 expression. NO donors stimulated the expression of peroxisome proliferator-activated receptor- and c-myc, both downstream genes of -catenin. They also induced the expression of polyoma enhancer activator 3 (PEA3) and increased its DNA-binding activity. To establish a role for PEA3 to -catenin-induced COX-2, we transfected RKO cells with -catenin and found that -catenin increased PEA3 expression. Also, there was higher PEA3 in immortal mouse colon epithelium cells (Apc^Min/+) compared with young adult mouse colon cells (Apc^+/+). Luciferase reporter assays revealed that, although several transcription factors/coactivator, acting alone or in synergistic combination, induced COX-2 promoter activity, PEA3 was one of the most potent. Interestingly, NO from NO donors or generated endogenously from transfected inducible nitric-oxide synthase, increased PEA3/p300-induced COX-2 promoter activity. We also found that an ETS site (-75/-72) and the NF-IL6 site were responsible for COX-2 activity induced by PEA3, PEA3/p300, and NO. Taken together, our results demonstrated that NO through -catenin signaling stimulated PEA3 to increase COX-2 activity. In addition, NO augmented the synergistic interaction between PEA3 and CBP/p300.

Received for publication, July 25, 2003 , and in revised form, February 17, 2004.

^* This work was supported by the NCI, National Institutes of Health, under contract NO1-CO-12400. 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: NCI, National Institutes of Health, Bldg. 538, Rm. 144, Frederick, MD 21702. Tel.: 301-846-5367; Fax: 301-846-6093; E-mail: phang{at}ncifcrf.gov.

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