title: Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage.
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 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Nabendu
authors.initials: N
authors.lastname: Murmu
authors.forename: Jesse
authors.initials: J
authors.lastname: Jung
authors.forename: Debnath
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
authors.forename: Terrence E
authors.initials: TE
authors.lastname: Riehl
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
authors.forename: Aubrey R
authors.initials: AR
authors.lastname: Morrison
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.forename: Brian K
authors.initials: BK
authors.lastname: Dieckgraefe
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
mesh_terms: D000818:Animals; D000067878:CELF Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects*; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000528:radiation effects*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000067878:CELF Proteins; C117363:CELF2 protein, human; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone