Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1

Dan A. Dixon, Glen C. Balch, Nancy Kedersha, Paul Anderson, Guy A. Zimmerman, R. Daniel Beauchamp, Stephen M. Prescott

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154 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)475-481
Number of pages7
JournalJournal of Experimental Medicine
Volume198
Issue number3
DOIs
StatePublished - Aug 4 2003

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Keywords

  • AU-rich element
  • COX-2
  • Cyclooxygenase-2
  • Prostaglandins
  • TIA-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Dixon, D. A., Balch, G. C., Kedersha, N., Anderson, P., Zimmerman, G. A., Beauchamp, R. D., & Prescott, S. M. (2003). Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. Journal of Experimental Medicine, 198(3), 475-481. https://doi.org/10.1084/jem.20030616