title: Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR.
abstract: 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.
authors.affiliation: Department of Internal Medicine and Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Jin
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.forename: Kyoung Min
authors.initials: KM
authors.lastname: Yang
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: 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*
chemical_list: 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