title: The extracellular signal-regulated kinase mitogen-activated protein kinase/ribosomal S6 protein kinase 1 cascade phosphorylates cAMP response element-binding protein to induce MUC5B gene expression via D-prostanoid receptor signaling.
abstract: Mucus hypersecretion is a prominent feature of respiratory diseases, and MUC5B is a major airway mucin. Mucin gene expression can be affected by inflammatory mediators, including prostaglandin (PG) D(2,) an inflammatory mediator synthesized by hematopoietic PGD synthase (H-PGDS). PGD(2) binds to either D-prostanoid receptor (DP1) or chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). We investigated the mechanisms by which PGD(2) induces MUC5B gene expression in airway epithelial cells. Western blot analysis showed that H-PGDS was highly expressed in nasal polyps. Similar results were obtained for PGD(2) expression. In addition, we could clearly detect the expressions of both H-PGDS and DP1 in nasal epithelial cells but not CRTH2. We demonstrated that PGD(2) increased MUC5B gene expression in normal human nasal epithelial cells as well as in NCI-H292 cells in vitro. S5751, a DP1 antagonist, inhibited PGD(2)-induced MUC5B expression, whereas a CRTH2 antagonist (OC0459) did not. These data suggest that PGD(2) induced MUC5B expression via DP1. Pretreatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) blocked both PGD(2)-induced ERK mitogen-activated protein kinase (MAPK) activation and MUC5B expression. Proximity ligation assays showed direct interaction between RSK1 and cAMP response element-binding protein (CREB). Stimulation with PGD(2) caused an increase in intracellular cAMP levels, whereas intracellular Ca(2+) did not have such an effect. PGD(2)-induced MUC5B mRNA levels were regulated by CREB via direct interaction with two cAMP-response element sites (-921/-914 and -900/-893). Finally, we demonstrated that PGD(2) can induce MUC5B overproduction via ERK MAPK/RSK1/CREB signaling and that DP1 receptor may have suppressive effects in controlling MUC5B overproduction in the airway.
authors.affiliation: The Airway Mucus Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Yeon Ho
authors.initials: YH
authors.lastname: Choi
authors.forename: Sang-Nam
authors.initials: SN
authors.lastname: Lee
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoyagi
authors.forename: Yasundo
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.forename: Boryung
authors.initials: B
authors.lastname: Park
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
mesh_terms: D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D055257:Mucin-5B / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015230:Prostaglandin D2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C432167:7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D005419:Flavonoids; D054834:Lipocalins; C524578:MUC5B protein, human; D055257:Mucin-5B; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013876:Thiophenes; C501562:prostanoid D receptor 1, human; D000242:Cyclic AMP; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C036293:prostaglandin D2 receptor