Robert Beauchamp
Principal Investigator
Last active: 10/31/2018

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

Dixon DA, Balch GC, Kedersha N, Anderson P, Zimmerman GA, Beauchamp RD, Prescott SM
J Exp Med. 2003 198 (3): 475-81

PMID: 12885872 · PMCID: PMC2194089 · DOI:10.1084/jem.20030616

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.

MeSH Terms (19)

Animals Cyclooxygenase 2 Fibroblasts Gene Expression Regulation, Enzymologic Humans Isoenzymes Membrane Proteins Mice Poly(A)-Binding Proteins Prostaglandin-Endoperoxide Synthases Protein Binding Protein Biosynthesis Proteins RNA, Messenger RNA-Binding Proteins RNA Processing, Post-Transcriptional Silencer Elements, Transcriptional T-Cell Intracellular Antigen-1 Tumor Cells, Cultured

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