title: Regulation of transforming growth factor-beta-dependent cyclooxygenase-2 expression in fibroblasts.
abstract: Abnormal transforming growth factor-beta (TGF-beta) signaling is a critical contributor to the pathogenesis of various human diseases ranging from tissue fibrosis to tumor formation. Excessive TGF-beta signaling stimulates fibrotic responses. Recent research has focused in the main on the antiproliferative effects of TGF-beta in fibroblasts, and it is presently understood that TGF-beta-stimulated cyclooxygenase-2 (COX-2) induction in fibroblasts is essential for antifibroproliferative effects of TGF-beta. Both TGF-beta and COX-2 have been implicated in tumor growth, invasion, and metastasis, and therefore tumor-associated fibroblasts are a recent topic of interest. Here we report the identification of positive and negative regulatory factors of COX-2 expression induced by TGF-beta as determined using proteomic approaches. We show that TGF-beta coordinately up-regulates three factors, heterogeneous nuclear ribonucleoprotein A/B (HNRPAB), nucleotide diphosphate kinase A (NDPK A), and nucleotide diphosphate kinase A (NDPK B). Functional pathway analysis showed that HNRPAB augments mRNA and protein levels of COX-2 and subsequent prostaglandin E(2) (PGE(2)) production by suppressing degradation of COX-2 mRNA. In contrast, NDPK A and NDPK B attenuated mRNA and protein levels of COX-2 by affecting TGF-beta-Smad2/3/4 signaling at the receptor level. Collectively, we report on a new regulatory pathway of TGF-beta in controlling expression of COX-2 in fibroblasts, which advances our understanding of pathophysiological mechanisms of TGF-beta.
authors.affiliation: Departments of Cardiovascular Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Aizawa
authors.forename: Daigo
authors.initials: D
authors.lastname: Sawaki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Munemasa
authors.forename: Junichi
authors.initials: J
authors.lastname: Ishida
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D012097:Repressor Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C077048:Hnrnpab protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C517939:Nme1 protein, mouse; D015232:Dinoprostone