TY - JOUR
T1 - TNF-α induces MUC1 gene transcription in lung epithelial cells
T2 - Its signaling pathway and biological implication
AU - Koga, Takeshi
AU - Kuwahara, Ippei
AU - Lillehoj, Erik P.
AU - Lu, Wenju
AU - Miyata, Takeshi
AU - Isohama, Yoichiro
AU - Kim, K. Chul
PY - 2007/9
Y1 - 2007/9
N2 - The current study was conducted to elucidate the mechanism through which TNF-α stimulates expression of MUC1, a membrane-tethered mucin. A549 human lung alveolar cells treated with TNF-α exhibited significantly higher MUC1 protein levels in detergent lysates compared with cells treated with vehicle alone. Increased MUC1 protein levels were correlated with significantly higher levels of MUC1 mRNA in TNF-α-treated cells compared with controls. However, TNF-α did not alter MUC1 transcript stability, implying increased de novo transcription induced by the cytokine. TNF-α increased MUC1 gene promoter activity in A549 cells transfected with a promoter-luciferase reporter plasmid. Both U0126, an inhibitor of MEK1/2, and dominant negative ERK1 prevented TNF-α-induced MUC1 promoter activation, and anti-TNFR1 antibody blocked TNF-α-stimulated ERK1/2 activation. MUC1 promoter activation by TNF-α also was blocked by mithramycin A, an inhibitor of Sp1, as well as either deletion or mutation of a putative Sp1 binding site in the MUC1 promoter located between nucleotides -99 and -90. TNF-α-stimulated binding of Sp1 to the MUC1 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay. We conclude that TNF-α induces MUC1 gene transcription through a TNFR1 → MEK1/2 → ERK1 → Sp1 pathway.
AB - The current study was conducted to elucidate the mechanism through which TNF-α stimulates expression of MUC1, a membrane-tethered mucin. A549 human lung alveolar cells treated with TNF-α exhibited significantly higher MUC1 protein levels in detergent lysates compared with cells treated with vehicle alone. Increased MUC1 protein levels were correlated with significantly higher levels of MUC1 mRNA in TNF-α-treated cells compared with controls. However, TNF-α did not alter MUC1 transcript stability, implying increased de novo transcription induced by the cytokine. TNF-α increased MUC1 gene promoter activity in A549 cells transfected with a promoter-luciferase reporter plasmid. Both U0126, an inhibitor of MEK1/2, and dominant negative ERK1 prevented TNF-α-induced MUC1 promoter activation, and anti-TNFR1 antibody blocked TNF-α-stimulated ERK1/2 activation. MUC1 promoter activation by TNF-α also was blocked by mithramycin A, an inhibitor of Sp1, as well as either deletion or mutation of a putative Sp1 binding site in the MUC1 promoter located between nucleotides -99 and -90. TNF-α-stimulated binding of Sp1 to the MUC1 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay. We conclude that TNF-α induces MUC1 gene transcription through a TNFR1 → MEK1/2 → ERK1 → Sp1 pathway.
KW - Mitogen-activated protein kinase
KW - Sp1
KW - Tumor necrosis factor-α
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U2 - 10.1152/ajplung.00491.2006
DO - 10.1152/ajplung.00491.2006
M3 - Article
C2 - 17575006
AN - SCOPUS:34548444561
SN - 1040-0605
VL - 293
SP - L693-L701
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 3
ER -