Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells

Modulation of cyclooxygenase-2 (COX-2) mRNA stability plays an important ro le in the regulation of its expression by oncogenic Ras, Here, we evaluate COX-2 mRNA stability in response to treatment with two known endogenous pro moters of gastrointestinal cancer, the bile acid (chenodeoxycholate; CD) an d ceramide. Treatment with CD and ceramide resulted in a 10-fold increase i n the level of COX-2 protein and a four-fold lengthening of the half-life o f COX-2 mRNA, COX-2 mRNA stability was assessed by Northern blot analysis a nd by evaluating the AU-rich element located in the COX-2 3'-UTR. A known i nhibitor 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. E xpression of a dominant-negative c-Jun N-terminal kinase (JNK) had no effec t on COX-2 mRNA stability in cells treated with CD or ceramide. We conclude that posttranscriptional mechanisms play an important role in the regulati on of COX-2 expression during carcinogenesis.