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

Research output: Contribution to journalArticle

152 Citations (Scopus)

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

Fingerprint

Cyclooxygenase 2
AU Rich Elements
Messenger RNA
Fibroblasts
RNA
Repressor Proteins
Polyribosomes
3' Untranslated Regions
Colonic Neoplasms
Prostaglandins
Carcinogenesis

Keywords

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

ASJC Scopus subject areas

  • 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

Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. / Dixon, Dan A.; Balch, Glen C.; Kedersha, Nancy; Anderson, Paul; Zimmerman, Guy A.; Beauchamp, R. Daniel; Prescott, Stephen M.

In: Journal of Experimental Medicine, Vol. 198, No. 3, 04.08.2003, p. 475-481.

Research output: Contribution to journalArticle

Dixon, DA, Balch, GC, Kedersha, N, Anderson, P, Zimmerman, GA, Beauchamp, RD & Prescott, SM 2003, 'Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1', Journal of Experimental Medicine, vol. 198, no. 3, pp. 475-481. https://doi.org/10.1084/jem.20030616
Dixon, Dan A. ; Balch, Glen C. ; Kedersha, Nancy ; Anderson, Paul ; Zimmerman, Guy A. ; Beauchamp, R. Daniel ; Prescott, Stephen M. / Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. In: Journal of Experimental Medicine. 2003 ; Vol. 198, No. 3. pp. 475-481.
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