Distinctive signaling pathways in the induction of airway MUC5B and -AC expression by phorbol 12-myristate 13-acetate and their implication in lung diseases

Daphne Yuan Chen Wu, Reen Wu, Sekhar P. Reddy, Yong Chan Lee, Mary Mann Jong Chang

Research output: Contribution to journalArticle

Abstract

Elevated expression of gel-forming MUC5AC and -5B genes is a major pathological feature of various airway diseases. Normally, MUC5B is expressed predominantly by submucosal gland mucous cells. However, trans-differentiation of MUC5B expression by surface airway epithelial cells occurs in various lung-diseased tissues. The nature of this phenomenon is not known. Phorbol 12-myristate 13-acetate (PMA) was found to be a potent stimulator of MUC5B gene expression under air-liquid interface conditions in three airway epithelial cell systems: primary cultures of normal human bronchial epithelial cells; an immortalized normal human bronchial epithelial cell line, HBE1; and a human lung adenocarcinoma cell line, A549. Stimulation was time- and dose-dependent, could be demonstrated by promoter-reporter gene transfection, and was sensitive to mithramycin A, suggesting the involvement of a specificity protein 1-based transcriptional mechanism in the stimulation. Both PMA-induced MUC5B message and promoter-reporter gene activity were specifically sensitive to inhibition of protein kinase C (PKC)-δ, which was further confirmed by the forced expression of the dominant negative mutant of PKC-δ. With regards to downstream transduction, PMA-induced MUC5B expression was sensitive to inhibitors and dominant negative expression of signaling molecules involved in the Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1-mediated c-Jun N-terminal kinase and p38 pathways. This is in contrast to the inhibition of PMA-induced MUC5AC expression by inhibitors of the Ras/epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) signaling pathway. These results demonstrated for the first time that PMA-stimulated expression of MUC5AC and -5B is regulated through distinctive EGFR/ERK-dependent and -independent signaling pathways.

Original languageEnglish (US)
Pages (from-to)100-103
Number of pages4
JournalJournal of Organ Dysfunction
Volume3
Issue number2
DOIs
StatePublished - 2007

Fingerprint

Lung Diseases
Acetates
Phosphotransferases
Epithelial Cells
Reporter Genes
Epidermal Growth Factor Receptor
Protein Kinase C
Mitogen-Activated Protein Kinase 8
MAP Kinase Signaling System
Extracellular Signal-Regulated MAP Kinases
Mutant Proteins
Mitogen-Activated Protein Kinases
Transfection
Gels
Air
phorbol-12-myristate
Gene Expression
Cell Line
Genes
Proteins

Keywords

  • Lung disease
  • Mucin genes
  • Phorbol 12-myristate 13-acetate
  • Signaling pathways

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Critical Care
  • Physiology
  • Molecular Biology

Cite this

Distinctive signaling pathways in the induction of airway MUC5B and -AC expression by phorbol 12-myristate 13-acetate and their implication in lung diseases. / Wu, Daphne Yuan Chen; Wu, Reen; Reddy, Sekhar P.; Lee, Yong Chan; Chang, Mary Mann Jong.

In: Journal of Organ Dysfunction, Vol. 3, No. 2, 2007, p. 100-103.

Research output: Contribution to journalArticle

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abstract = "Elevated expression of gel-forming MUC5AC and -5B genes is a major pathological feature of various airway diseases. Normally, MUC5B is expressed predominantly by submucosal gland mucous cells. However, trans-differentiation of MUC5B expression by surface airway epithelial cells occurs in various lung-diseased tissues. The nature of this phenomenon is not known. Phorbol 12-myristate 13-acetate (PMA) was found to be a potent stimulator of MUC5B gene expression under air-liquid interface conditions in three airway epithelial cell systems: primary cultures of normal human bronchial epithelial cells; an immortalized normal human bronchial epithelial cell line, HBE1; and a human lung adenocarcinoma cell line, A549. Stimulation was time- and dose-dependent, could be demonstrated by promoter-reporter gene transfection, and was sensitive to mithramycin A, suggesting the involvement of a specificity protein 1-based transcriptional mechanism in the stimulation. Both PMA-induced MUC5B message and promoter-reporter gene activity were specifically sensitive to inhibition of protein kinase C (PKC)-δ, which was further confirmed by the forced expression of the dominant negative mutant of PKC-δ. With regards to downstream transduction, PMA-induced MUC5B expression was sensitive to inhibitors and dominant negative expression of signaling molecules involved in the Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1-mediated c-Jun N-terminal kinase and p38 pathways. This is in contrast to the inhibition of PMA-induced MUC5AC expression by inhibitors of the Ras/epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) signaling pathway. These results demonstrated for the first time that PMA-stimulated expression of MUC5AC and -5B is regulated through distinctive EGFR/ERK-dependent and -independent signaling pathways.",
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