Glucocorticoid inhibition of human SP-A1 promoter activity in NCI-H441 cells.
Glucocorticoids have complex effects on human surfactant protein (SP) SP-A1 and SP-A2 gene expression that occur at both transcriptional and post-transcriptional levels. In the lung adenocarcinoma cell line NCI-H441, dexamethasone causes a dose-dependent decrease in total SP-A mRNA levels and inhibits SP-A gene transcription. In this study, a deletional analysis of the SP-A1 promoter was performed in order to identify cis-acting elements that mediate dexamethasone responsiveness in NCI-H441 cells. The region -32/+63 relative to the start of SP-A1 transcription mediated both basal promoter activity and dexamethasone repression of transcription. Removal of the region +18/+63 abolished dexamethasone responsiveness, indicating that sequences within this region are necessary for the inhibitory effect. Furthermore, the region -32/+63 formed a sequence-specific DNA-protein complex with NCI-H441 nuclear extract. This DNA-protein complex was induced by dexamethasone exposure and its formation was mediated partially by sequences within the region +26/+63.
Hoover
R R
RR
Department of Cellular and Molecular Physiology, P.O. Box 850, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Thomas
K H
KH
Floros
J
J
D001483:Base Sequence; D001667:Binding, Competitive; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D008175:Lung Neoplasms; D008970:Molecular Weight; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D011510:Proteolipids / Q000235:genetics*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; C445842:SFTPA1 protein, human; C445843:SFTPA2 protein, human; D003907:Dexamethasone; D004247:DNA