Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage

Nabendu Murmu, Jesse Jung, Debnath Mukhopadhyay, Courtney W. Houchen, Terrence E. Riehl, William F. Stenson, Aubrey R. Morrison, Thiruvengadam Arumugam, Brian K. Dieckgraefe, Shrikant Anant

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Damage to intestinal epithelium limits the use of ionizing radiation (IR) in cancer therapy. Prostaglandins (PGs), generated through the action of cyclooxygenase-1 (COX-1) and COX-2 protect the intestinal stem cells from IR. In previous studies, we demonstrated that the RNA-binding protein CUGBP2 regulates the stability and translation of COX-2 mRNA by interacting with AU-rich sequences in 3′ UTR. Here, we demonstrate a dynamic antagonistic relationship between CUGBP2 and COX-2. Both CUGBP2 and COX-2 are rapidly induced after IR in intestinal crypt epithelial cells in mice, but CUGBP2 protein expression is observed immediately and COX-2 protein expression is delayed. In contrast, administration of bacterial lipopolysaccharide induced COX-2 expression and PGE2, resulting in the inhibition of CUGBP2 expression and radioprotection of the intestine. These effects were reversed by NS398, a COX-2-specific inhibitor, suggesting that lipopolysaccharide-mediated inhibition of CUGBP2 is a PG-dependent mechanism. Furthermore, CUGBP2 expression is higher in COX-1-/- and COX-2-/- mice than wild-type controls at basal conditions, which is further increased after IR.

Original languageEnglish
Pages (from-to)13873-13878
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number38
DOIs
StatePublished - Sep 21 2004

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