The Journal of Experimental Medicine
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Published online 28 July 2003 doi:10.1084/jem.20030616
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© Rockefeller University Press, 0022-1007/2003/8/475 $5.00
The Journal of Experimental Medicine, Volume 198, Number 3, 475-481

Brief Definitive Report

 Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1

Dan A. Dixon1, Glen C. Balch1, Nancy Kedersha4, Paul Anderson4, Guy A. Zimmerman2, R. Daniel Beauchamp1 and Stephen M. Prescott3

1 Surgical Oncology Research Laboratory, Departments of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232
2 Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
3 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
4 Division of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, MA 02115

Address correspondence to Dan A. Dixon, Surgical Oncology Research Laboratory, Vanderbilt University Medical Center, D-2300 MCN, 1161 21st Ave. S., Nashville, TN 37232-2733. Phone: 615-322-5244; Fax: 615-322-6174; email: dan.dixon{at}vanderbilt.edu

The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in inflammatory states, and COX-2 overexpression plays a key role in carcinogenesis. To understand the mechanisms regulating COX-2 expression, we examined its posttranscriptional regulation mediated through the AU-rich element (ARE) within the COX-2 mRNA 3'-untranslated region (3'UTR). RNA binding studies, performed to identify ARE-binding regulatory factors, demonstrated binding of the translational repressor protein TIA-1 to COX-2 mRNA. The significance of TIA-1-mediated regulation of COX-2 expression was observed in TIA-1 null fibroblasts that produced significantly more COX-2 protein than wild-type fibroblasts. However, TIA-1 deficiency did not alter COX-2 transcription or mRNA turnover. Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo. These findings implicate that TIA-1 functions as a translational silencer of COX-2 expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia.

Key Words: COX-2 • cyclooxygenase-2 • prostaglandins • TIA-1 • AU-rich element


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