Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.
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.
Dixon
Dan A
DA
Surgical Oncology Research Laboratory, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-2733, USA. dan.dixon@vanderbilt.edu
Balch
Glen C
GC
Kedersha
Nancy
N
Anderson
Paul
P
Zimmerman
Guy A
GA
Beauchamp
R Daniel
RD
Prescott
Stephen M
SM
D000818:Animals; D051546:Cyclooxygenase 2; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D039102:Poly(A)-Binding Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D037941:Silencer Elements, Transcriptional; D000074019:T-Cell Intracellular Antigen-1; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008565:Membrane Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C499367:Tia1 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases