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 language | English (US) |
|---|---|
| Pages (from-to) | 100-103 |
| Number of pages | 4 |
| Journal | Journal of Organ Dysfunction |
| Volume | 3 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2007 |
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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 journal › Article
}
TY - JOUR
T1 - Distinctive signaling pathways in the induction of airway MUC5B and -AC expression by phorbol 12-myristate 13-acetate and their implication in lung diseases
AU - Wu, Daphne Yuan Chen
AU - Wu, Reen
AU - Reddy, Sekhar P.
AU - Lee, Yong Chan
AU - Chang, Mary Mann Jong
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
KW - Lung disease
KW - Mucin genes
KW - Phorbol 12-myristate 13-acetate
KW - Signaling pathways
UR - http://www.scopus.com/inward/record.url?scp=34249785383&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249785383&partnerID=8YFLogxK
U2 - 10.1080/17471060601152364
DO - 10.1080/17471060601152364
M3 - Article
AN - SCOPUS:34249785383
VL - 3
SP - 100
EP - 103
JO - Journal of Organ Dysfunction
JF - Journal of Organ Dysfunction
SN - 1747-1060
IS - 2
ER -