Inhibition of cyclooxygenase-2 gene expression by p53

Kotha Subbaramaiah, Nasser Altorkil, Wen Jing Chung, Juan R. Mestre, Anu Sampat, Andrew J. Dannenberg

Research output: Contribution to journalArticle

327 Scopus citations

Abstract

Oncogenes enhance the expression of cyclooxygenase (Cox)-2, but interactions between tumor suppressor genes and Cox-2 have not been studied. In the present work, we have compared the levels of Cox-2 and the production of prostaglandin E2 in mouse embryo fibroblasts that do not express any p53 ((10)1) versus the same cell line ((10.1)Val5) engineered to overexpress wild-type (wt) p53 at 32 °C or mutant p53 at 39 °C. Cells expressing wt p53 showed about a 10-fold decrease in synthesis of prostaglandin E2 compared with those expressing mutant p53. Levels of Cox-2 protein and mRNA were markedly suppressed by wt p53 but not by mutant p53. Nuclear run-offs revealed decreased rates of Cox-2 transcription in cells expressing wt p53. The activity of the Cox-2 promoter was reduced by 85% in cells expressing wt p53 but was reduced only by 30% in cells expressing mutant p53 compared with cells null for p53. The effect of p53 on the suppression of Cox-2 promoter activity was localized to the first 40 base pairs 5' from the transcription start site. Electrophoretic mobility shift assay revealed that p53 competed with TATA-binding protein for binding to mouse Cox-2 or human Cox-2 promoter extending from -50 to +52 base pairs. The results of this study suggest that interactions between p53 and Cox-2 could be important for understanding why levels of Cox-2 are undetectable in normal cells and increased in many tumors.

Original languageEnglish (US)
Pages (from-to)10911-10915
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number16
DOIs
StatePublished - Apr 16 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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