Abstract
MUC5B is a major mucin of the human respiratory tract, and it is not clear how MUC5B expression is regulated in various airway diseases. The goal of this study was to determine the mechanisms by which 17beta-estradiol induces MUC5B gene expression in airway epithelial cells. It was found that E2, a sex hormone, stimulates MUC5B gene overexpression by interaction with estrogen receptor alpha (ERalpha) and by acting through extracellular signal-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK). Pretreatment with ER antagonist ICI 182,780 blocked both E2-induced ERK1/2-MAPK activation and MUC5B gene expression. It was also found that the activation of p90 ribosomal S 6 protein kinase 1 (RSK1), cAMP-response element-binding protein (CREB), and cAMP-response element (CRE) (-956 region of the MUC5B promoter)-responsive signaling cascades via ERK1/2 MAPK are crucial aspects of the intracellular mechanisms that mediate MUC5B gene expression. Taken together, these studies give additional insights into the molecular mechanism of hormone-induced MUC5B gene expression and enhance our understanding of abnormal mucin secretion in response to hormonal imbalances.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Epithelial Cells / cytology
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Epithelial Cells / metabolism*
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Estradiol / analogs & derivatives
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Estradiol / pharmacology*
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha / metabolism
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Female
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Fulvestrant
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Humans
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Male
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mucin-5B / biosynthesis*
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Respiratory Mucosa / cytology
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Respiratory Mucosa / metabolism*
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Response Elements / physiology
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Substances
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Estrogen Antagonists
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Estrogen Receptor alpha
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MUC5B protein, human
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Mucin-5B
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Fulvestrant
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Estradiol
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RPS6KA1 protein, human
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Ribosomal Protein S6 Kinases, 90-kDa
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3