Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage.
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.
Murmu
Nabendu
N
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Jung
Jesse
J
Mukhopadhyay
Debnath
D
Houchen
Courtney W
CW
Riehl
Terrence E
TE
Stenson
William F
WF
Morrison
Aubrey R
AR
Arumugam
Thiruvengadam
T
Dieckgraefe
Brian K
BK
Anant
Shrikant
S
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*
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