Document Detail

TNF-alpha induces MUC1 gene transcription in lung epithelial cells: its signaling pathway and biological implication.
MedLine Citation:
PMID:  17575006     Owner:  NLM     Status:  MEDLINE    
The current study was conducted to elucidate the mechanism through which TNF-alpha stimulates expression of MUC1, a membrane-tethered mucin. A549 human lung alveolar cells treated with TNF-alpha 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-alpha-treated cells compared with controls. However, TNF-alpha did not alter MUC1 transcript stability, implying increased de novo transcription induced by the cytokine. TNF-alpha 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-alpha-induced MUC1 promoter activation, and anti-TNFR1 antibody blocked TNF-alpha-stimulated ERK1/2 activation. MUC1 promoter activation by TNF-alpha 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-alpha-stimulated binding of Sp1 to the MUC1 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay. We conclude that TNF-alpha induces MUC1 gene transcription through a TNFR1 --> MEK1/2 --> ERK1 --> Sp1 pathway.
Takeshi Koga; Ippei Kuwahara; Erik P Lillehoj; Wenju Lu; Takeshi Miyata; Yoichiro Isohama; K Chul Kim
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-06-15
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  293     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-30     Completed Date:  2007-10-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L693-701     Citation Subset:  IM    
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
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MeSH Terms
Antigens, Neoplasm / genetics*,  metabolism
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Epithelial Cells / drug effects,  metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Lung / cytology*,  drug effects,  metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism
Mucins / genetics*,  metabolism
Promoter Regions, Genetic / genetics
Protein Binding / drug effects
RNA Stability / drug effects
RNA, Messenger / genetics,  metabolism
Receptors, Tumor Necrosis Factor, Type I / metabolism
Signal Transduction / drug effects*
Sp1 Transcription Factor / metabolism
Time Factors
Transcription, Genetic / drug effects*
Tumor Necrosis Factor-alpha / pharmacology*
Grant Support
Reg. No./Substance:
0/Antigens, Neoplasm; 0/MUC1 protein, human; 0/Mucin-1; 0/Mucins; 0/RNA, Messenger; 0/Receptors, Tumor Necrosis Factor, Type I; 0/Sp1 Transcription Factor; 0/Tumor Necrosis Factor-alpha; EC Protein Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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