Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells

Zhonghua Zhang, Hongmiao Sheng, Jinyi Shao, R. Daniel Beauchampt, Raymond N. DuBois

    Research output: Contribution to journalArticlepeer-review

    66 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)523-530
    Number of pages8
    JournalNeoplasia
    Volume2
    Issue number6
    DOIs
    StatePublished - 2000

    Keywords

    • Cyclooxygenase
    • Gene regulation
    • MAPK
    • Stabilization

    ASJC Scopus subject areas

    • Cancer Research

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