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

Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13873-8. doi: 10.1073/pnas.0406066101. Epub 2004 Sep 9.


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 PGE(2), 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CELF Proteins
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone / metabolism*
  • Dose-Response Relationship, Radiation
  • Gene Expression Regulation, Enzymologic / radiation effects*
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / radiation effects*
  • Isoenzymes / deficiency
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Prostaglandin-Endoperoxide Synthases / deficiency
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / metabolism*


  • CELF Proteins
  • CELF2 protein, human
  • Isoenzymes
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Dinoprostone