Distinctive Signaling Pathways in the Induction of Airway MUC5B and MUC5AC Expression by PMA and Its Implication in Lung Diseases
Elevated expression of gel forming MUC5AC and MUC5B genes is a major pathological feature in various airway diseases. Normally, MUC5B is expressed predominately 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-mynstate 13-acetate (PMA), 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; an immortalized normal bronchial epithelial cell line, HBB1; 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 Sp1 based transchptional mechanism in the stimulation. Both PMA-induced MUC5B message and promoter-reporter gene activity were specifically sensitive to inhibition of PKC δ, which was farther confirmed by the forced expression of dominant negative mutant of PKC δ. In regards to downstream transduction, PMA-induced MUC5B expression was sensitive to inhibitors and dominant negative expression of signaling molecules involved in Ras/MEKK1-mediated JNK and p38 pathways. This is in contrast to the inhibition of PMA-induced MUC5AC expression by inhibitors of the Ras/EGFR/ERK signaling pathway. These results demonstrated for the first time that PMA-stimulated MUC5AC and MUC5B expressions are regulated through distinctive EGFR/ERK-dependent and -independent signaling pathways.
Daphne Yuan-chen Wu Reen Wu Sekhar P. Reddy Yong Chan Lee Mary Mann-Jong Chang
Center for Comparative Respiratory Biology and Medicine, University of California, Davis, California Department of Environmental Health Sciences, School of Public of Health, The Johns Hopkins Universit
国际会议
上海
英文
54-58
2006-11-16（万方平台首次上网日期，不代表论文的发表时间）