Caveolin-1 Transcriptional Regulation in Lung Cell Lines

Boston University Medical Campus, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The functions of caveolin-1 include modulation of signaling events, cholesterol trafficking, and tumor suppression. There are two protein isoforms of caveolin-1 (alpha and beta) produced by two different mRNAs. Immunohistochemistry shows that caveolin-1alpha is expressed in developing mouse lung endothelial cells but not developing epithelial cells. In adult lung, caveolin-1alpha is present in both cell types. In caveolin-1 knockout mice, only the lung has structural abnormalities. This phenotype appears 2-4 months postnatally, around the same developmental time caveolin-1alpha is first expressed in lung epithelium. I hypothesize that transcription of caveolin-1 is differentially regulated in lung endothelial and epithelial cells. My preliminary data shows that transcriptional activity of the 1.3 kb caveolin-1 promoter is 7.5 fold higher in lung epithelial than lung endothelial cells. Deletion fragments show that between -265 and -865 bps expression is increased in the epithelial, but not endothelial cell line, suggesting an epithelial specific enhancer in this area. I will address my hypothesis with two specific aims: 1) Characterize regulatory elements that differentiate between epithelial and endothelial cells by performing further deletion studies. I will use computer algorithms to identify putative enhancer sites that will be tested by mobility shift assays. 2) Prove these sites are functional by performing mutational analysis of binding sites and testing suspect transcription factors in co-expression studies. These findings will be used in future experiments to evaluate the role of caveolin-1 in lung and ultimately to understand better the regulation of the alveolar type I cell phenotype.