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

Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells.

Zhang Z, Sheng H, Shao J, Beauchamp RD, DuBois RN
Neoplasia. 2000 2 (6): 523-30

PMID: 11228545 · PMCID: PMC1508084 · DOI:10.1038/sj.neo.7900117

Modulation of cyclooxygenase-2 (COX-2) mRNA stability plays an important role in the regulation of its expression by oncogenic Ras. Here, we evaluate COX-2 mRNA stability in response to treatment with two known endogenous promoters of gastrointestinal cancer, the bile acid (chenodeoxycholate; CD) and ceramide. Treatment with CD and ceramide resulted in a 10-fold increase in the level of COX-2 protein and a four-fold lengthening of the half-life of COX-2 mRNA. COX-2 mRNA stability was assessed by Northern blot analysis and by evaluating the AU-rich element located in the COX-2 3'-UTR. A known inhibitor of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK), PD98059, reversed the effects of CD or ceramide to stabilize COX-2 mRNA. Overexpression of a dominant-negative ERK-1 or ERK-2 protein also led to destabilization of COX-2 mRNA. Treatment with a p38 MAPK inhibitor, PD169316, or transfection with a dominant-negative p38 MAPK construct reversed the effect of CD or ceramide to stabilize COX-2 mRNA. Expression of a dominant-negative c-Jun N-terminal kinase (JNK) had no effect on COX-2 mRNA stability in cells treated with CD or ceramide. We conclude that posttranscriptional mechanisms play an important role in the regulation of COX-2 expression during carcinogenesis.

MeSH Terms (18)

Animals Cell Line Ceramides Chenodeoxycholic Acid Cyclooxygenase 2 Gene Expression Regulation, Enzymologic Genes, Dominant Intestinal Mucosa Isoenzymes Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Prostaglandin-Endoperoxide Synthases Rats RNA, Messenger RNA Processing, Post-Transcriptional

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