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
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
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DOI：
10.1074/jbc.m111.247684
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发表时间：
2011-09-30
影响因子：
4.8
通讯作者：
Yoon, Joo-Heon
中科院分区：
文献类型：
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作者：
Choi, Yeon Ho;Lee, Sang-Nam;Yoon, Joo-Heon
粘液高分泌是呼吸道疾病的显著特征，而MUC 5 B是一种主要的气道粘蛋白。粘蛋白基因表达可受炎症介质影响，包括前列腺素（PG）D-2，一种由造血PGD合酶（H-PGDS）合成的炎症介质。PGD（2）与D-前列腺素受体（DP 1）或在辅助性T细胞2型（CRTH 2）上表达的化学引诱物受体同源分子结合。我们研究了PGD（2）诱导气道上皮细胞MUC 5 B基因表达的机制。Western blot分析显示H-PGDS在鼻息肉组织中呈高表达。对于PGD 2表达获得了类似的结果。此外，我们可以清楚地检测到H-PGDS和DP 1在鼻上皮细胞中的表达，但不能检测到CRTH 2。我们证明PGD（2）在体外增加了正常人鼻上皮细胞和NCI-H292细胞中MUC 5 B基因的表达。DP 1拮抗剂S5751抑制PGD（2）诱导的MUC 5 B表达，而CRTH 2拮抗剂（OC 0459）则无此作用。这些数据表明PGD（2）通过DP 1诱导MUC 5 B表达。细胞外信号调节激酶（ERK）抑制剂（PD 98059）预处理可阻断PGD（2）诱导的ERK丝裂原活化蛋白激酶（MAPK）激活和MUC 5 B表达。邻位连接分析显示RSK 1和cAMP反应元件结合蛋白（CREB）之间的直接相互作用。用PGD 2刺激引起细胞内cAMP水平的增加，而细胞内Ca 2+没有这样的作用。CREB通过与两个cAMP反应元件位点（-921/-914和-900/-893）直接相互作用调节PGD 2诱导的MUC 5 B mRNA水平。最后，我们证实PGD（2）可通过ERK MAPK/RSK 1/CREB信号通路诱导MUC 5 B的过度表达，并且DP 1受体可能在控制气道中MUC 5 B的过度表达中具有抑制作用。
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 PGD2 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 PGD2 caused an increase in intracellular cAMP levels, whereas intracellular Ca2+ did not have such an effect. PGD2-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.