Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR.
We investigated the effect of thalidomide on transcriptional and post-transcriptional cyclooxygenase-2 (COX-2) expression, including a pathway leading to COX-2 mRNA destabilization. We found that thalidomide inhibited the interleukin-1beta (IL-1beta)-mediated induction of COX-2 protein and mRNA in Caco-2 cells. Transient transfection with a COX-2 promoter construct demonstrated that thalidomide did not affect IL-1beta-induced transcriptional activation of COX-2, although it did decrease the stability of COX-2 mRNA and suppress IL-1beta-induced cytoplasmic shuttling of an mRNA stabilizing protein, HuR. Thalidomide also suppressed IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation, while a p38 MAPK inhibitor destabilized COX-2 mRNA and the cytoplasmic shuttling of HuR induced by IL-1beta. These data suggest that one of the molecular mechanisms of thalidomide may be destabilization of COX-2 mRNA through inhibition of cytoplasmic shuttling of HuR and p38 MAPK.
Jin
Soo Hyun
SH
Department of Internal Medicine and Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Kim
Tae Il
TI
Yang
Kyoung Min
KM
Kim
Won Ho
WH
D000954:Antigens, Surface / Q000378:metabolism*; D018938:Caco-2 Cells; D051546:Cyclooxygenase 2 / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013792:Thalidomide / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D016601:RNA-Binding Proteins; D013792:Thalidomide; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580