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

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Abstract

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.

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Abbreviations

COX-2:

Cyclooxygenase-2

PPAR:

Peroxisome proliferator-activated receptor

RXR:

Retinoic acid receptor

tRA:

All-trans-retinoic acid

9cRA:

9-Cis-retinoic acid

DR1:

Direct repeat 1

cPGI:

Carbaprostacylin

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Acknowledgment

This work was supported by National Research Foundation of Korea Grant funded by the Korean Government (313-2008-2-C00642). Authors thank members of the Lim laboratory for various technical supports.

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Authors and Affiliations

  1. Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, IBST, RCTC, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul, 143-701, Korea

    Kyuyong Han & Hyunjung J. Lim

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Irene Moon

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  1. Kyuyong Han
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  2. Irene Moon
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Correspondence to Hyunjung J. Lim.

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Han, K., Moon, I. & Lim, H.J. All-trans- and 9-cis-retinoic acids activate the human cyclooxynase-2 gene: a role for DR1 as RARE or RXRE. Mol Biol Rep 38, 833–840 (2011). https://doi.org/10.1007/s11033-010-0173-4

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