TY - JOUR
T1 - Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage
AU - Murmu, Nabendu
AU - Jung, Jesse
AU - Mukhopadhyay, Debnath
AU - Houchen, Courtney W.
AU - Riehl, Terrence E.
AU - Stenson, William F.
AU - Morrison, Aubrey R.
AU - Arumugam, Thiruvengadam
AU - Dieckgraefe, Brian K.
AU - Anant, Shrikant
PY - 2004/9/21
Y1 - 2004/9/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=4644353518&partnerID=8YFLogxK
U2 - 10.1073/pnas.0406066101
DO - 10.1073/pnas.0406066101
M3 - Article
C2 - 15358864
AN - SCOPUS:4644353518
SN - 0027-8424
VL - 101
SP - 13873
EP - 13878
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -