Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate.
Elevated expression of gel-forming mucin (MUC) genes MUC5AC and MUC5B is a major pathological feature in various airway diseases. In this study, we show that phorbol 12-myristate 13-acetate (PMA) is a potent stimulator for MUC5B gene expression under air-liquid interface conditions in three airway epithelial cell systems: primary cultures of normal human bronchial epithelial cells, the immortalized normal bronchial epithelial cell line HBE1, and the 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. PMA-induced MUC5B message and promoter-reporter gene activity were specifically sensitive to inhibition of protein kinase C delta, which was further confirmed by the forced expression of dominant-negative mutant of protein kinase C delta. Regarding downstream transduction, PMA-induced MUC5B expression was sensitive to inhibitors and dominant-negative expression of signaling molecules involved in Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase1-mediated c-Jun N-terminal kinase and p38 pathways. This contrasted with the inhibition of PMA-induced MUC5AC expression by inhibitors of the Ras/epidermal growth factor receptor/extracellular regulated kinase signaling pathway. These results demonstrate for the first time that PMA-stimulated MUC5AC and MUC5B expressions are regulated through distinctive epidermal growth factor receptor/extracellular regulated kinase-dependent and -independent signaling pathways.
Yuan-Chen Wu
Daphne
D
Center for Comparative Respiratory Biology and Medicine, Genome and Biomedical Science Facility, Suite 6510 University of California, Davis, 451 East Health Sciences Dr., Davis, CA 95616, USA.
Wu
Reen
R
Reddy
Sekhar P
SP
Lee
Yong Chan
YC
Chang
Mary Mann-Jong
MM
D001980:Bronchi; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea
C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate