All-trans- and 9-cis-retinoic acids activate the human cyclooxynase-2 gene: a role for DR1 as RARE or RXRE

• Published in: Molecular biology reports 2011-02, Vol.38 (2), p.833-840
• Main Authors: Han, Kyuyong, Moon, Irene, Lim, Hyunjung J
• Format: Article
• Language: English
• Subjects: Acids; Animal Anatomy; Animal Biochemistry; Animals; Binding Sites; Biomedical and Life Sciences; Biosynthesis; Cell Line, Tumor; Cofactors; COX-2; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; DR1; Enzyme Activation; Enzymes; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes; Histology; Humans; Life Sciences; Mice; Mice, Inbred ICR; Molecular biology; Morphology; Peroxisome proliferator-activated receptors; PPAR gamma - metabolism; PPARδ; Promoters; Protein Structure, Tertiary; RAR; Retinoic acid; Retinoic acids; Retinoid X receptors; RXR; Tretinoin - metabolism
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-010-0173-4

The human COX-2 promoter contains a direct repeat 1 (DR1) which was shown to confer responsiveness to PPARs. We found that in AN₃CA and F9 cells, this hCOX-2 DR1 mediates responsiveness to all-trans-retinoic acid (tRA) or 9-cis-retinoic acid (9cRA), but this effect was suppressed by PPARδ. Truncated PPARδ lacking the activation domain AF2 cannot suppress RA-induced activation of the hCOX-2 gene via DR1, suggesting that cofactor recruitment by AF2 is required for the suppression by PPARδ. Gel shift assay showed that PPAR/RXR, RARβ/RXR, and RXR/RXR, bind to hCOX-2 DR1, revealing the promiscuity of this DR1. Particularly, RXR homodimer was able to bind to this DR1 only in the presence of 9cRA. Our results established that tRA and 9cRA are potent inducers of hCOX-2 and that the hCOX-2 DR1 could either serve as RARE or RXRE depending on cellular contexts.