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Am J Physiol Lung Cell Mol Physiol (April 22, 2005). doi:10.1152/ajplung.00040.2005
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Submitted on January 20, 2005
Accepted on April 21, 2005

Neutrophil elastase stimulates MUC1 gene expression through increased Sp1 binding to the MUC1 promoter

Ippei Kuwahara1, Erik P Lillehoj1, Akinori Hisatsune1, Wenju Lu1, Yoichiro Isohama2, Takeshi Miyata2, and K. Chul Kim1*

1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
2 Department of Chemico-Pharmacology, Kumamoto University Graduate School of Medicine and Pharmacy, Kumamoto, Japan

* To whom correspondence should be addressed. E-mail: kkim{at}umaryland.edu.

We previously reported that MUC1 was a cell surface receptor for Pseudomonas aeruginosa and binding of bacteria to cells was significantly reduced by pretreatment with neutrophil elastase (NE) (Lillehoj EP, Hyun SW, Kim BT, Zhang XG, Lee DI, Rowland S, and Kim KC. Am J Physiol Lung Cell Mol Physiol 280: L181-L187, 2001). The current study was conducted to ascertain the effects of NE on MUC1 gene transcription, and MUC1 protein synthesis and degradation. A549 human lung carcinoma cells treated with NE exhibited significantly higher MUC1 protein levels in detergent lysates compared with cells treated with vehicle alone. In addition, MUC1 protein shed into cell-conditioned medium was rapidly and completely degraded by NE. Actinomycin D blocked the NE-stimulated increase in MUC1 protein expression suggesting a mechanism of increased gene transcription, which was confirmed by measurement of quantitatively greater MUC1 mRNA levels in NE-treated cells compared with controls. However, NE did not alter MUC1 mRNA stability implying increased de novo transcription induced by the protease. NE increased promoter activity in A549 cells transfected with a MUC1 gene promoter-luciferase reporter plasmid. This effect of NE was completely blocked by mithramycin A, an inhibitor of Sp1, as well as the mutation of one of the putative Sp1 binding sites in the MUC1 promoter located at -99/-90 relative to the transcription initiation site. Electrophoretic mobility shift assay revealed that NE enhanced the binding of Sp1 to this 10 bp segment in a time-dependent manner. These results indicate that the increase in MUC1 gene transcription by NE is mediated through an increase in Sp1 binding to the -99/-90 segment of the MUC1 promoter.




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