This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0176OCv1 34/3/338    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Rose, M. C. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Rose, M. C.

Dexamethasone-Mediated Repression of MUC5AC Gene Expression in Human Lung Epithelial Cells

Center for Genetic Medicine Research, and Center for Cancer and Immunology Research, Children's Research Institute; and Department of Pediatrics, and Department of Biochemistry and Molecular Biology, George Washington University School of Medicine and Health Sciences, Washington, DC

Correspondence and requests for reprints should be addressed to Mary C. Rose, Ph.D., Center for Genetic Medicine Research, Children's Research Institute, Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC 20010. E-mail: mrose{at}cnmcresearch.org

Glucocorticoids regulate gene expression via binding of the ligand-activated glucocorticoid receptor (GR) to glucocorticoid-responsive elements (GRE) in target gene promoters. The MUC5AC gene, which encodes the protein backbone of an abundant secreted airway mucin, has several putative GRE cis-elements in its 5' sequence. Mechanism(s) whereby glucocorticoids regulate mucin genes have not previously been described. In this study, the glucocorticoid dexamethasone (Dex) decreased MUC5AC mRNA abundance in A549 and NCI-H292 cell lines and primary differentiated normal bronchial epithelial cells by 50–80%, suggesting a common mechanism of MUC5AC gene repression in human lung epithelial cells. Kinetic analyses showed that MUC5AC mRNA was not significantly decreased until 6 h after Dex exposure, and that nuclear translocation of GR was biphasic, suggesting that Dex-mediated cis-repression of MUC5AC gene expression was a delayed response of GR translocation. Transfection analyses demonstrated that Dex transcriptionally repressed the MUC5AC promoter. Electrophoretic mobility shift assays with wild-type and mutant oligonucleotide probes showed that GR bound to two GRE cis-sites (nucleotides –930 to –912 and –369 to –351) in the MUC5AC promoter. Analyses of mutated MUC5AC promoter constructs demonstrated that NF-B cis-sites were not involved in Dex-mediated repression of MUC5AC. Dex did not alter mRNA stability of MUC5AC transcripts. Taken together, the data indicate that Dex transcriptionally mediates repression of MUC5AC gene expression in human lung epithelial cells at quiescent states after binding of GR to one or more GRE cis-elements in the MUC5AC promoter.

Key Words: MUC5AC mucin gene • gene repression • dexamethasone • lung cells • glucocorticoids

This article has been cited by other articles:

				H.-P. Hauber, T. Goldmann, E. Vollmer, B. Wollenberg, H.-L. Hung, R. C. Levitt, and P. Zabel LPS-induced mucin expression in human sinus mucosa can be attenuated by hCLCA inhibitors Innate Immunity, April 1, 2007; 13(2): 109 - 116. [Abstract] [PDF]