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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.

 Yeon Ho Choi  ;  Sang-Nam Lee  ;  Hiroki Aoyagi  ;  Yasundo Yamasaki  ;  Jung-Yoon Yoo  ;  Boryung Park  ;  Dong Min Shin  ;  Ho-Geun Yoon  ;  Joo-Heon Yoon 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.286(39) : 34199-34214, 2011 
Journal Title
Issue Date
Cell Line ; Cyclic AMP/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism* ; Enzyme Activation/drug effects ; Enzyme Activation/physiology ; Epithelial Cells/cytology ; Epithelial Cells/metabolism* ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Flavonoids/pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology* ; Humans ; Intramolecular Oxidoreductases/metabolism ; Lipocalins/metabolism ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Mucin-5B/biosynthesis* ; Phosphorylation/drug effects ; Phosphorylation/physiology ; Prostaglandin D2/metabolism ; Receptors, Immunologic/antagonists & inhibitors ; Receptors, Immunologic/metabolism ; Receptors, Prostaglandin/antagonists & inhibitors ; Receptors, Prostaglandin/metabolism* ; Respiratory Mucosa/cytology ; Respiratory Mucosa/metabolism* ; Response Elements/physiology ; Ribosomal Protein S6 Kinases, 90-kDa/metabolism* ; Thiophenes/pharmacology
DP1 ; MUC5B ; Prostaglandin D2
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.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Research Center for Human Natural Defense System (생체방어연구센터) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Park, Bo Ryung(박보령)
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Yoo, Jung Yoon(유정윤) ORCID logo https://orcid.org/0000-0001-9366-3863
Yoon, Joo Heon(윤주헌)
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Lee, Sang Nam(이상남)
Choi, Yeon Ho(최연호)
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