Glucocorticoid increases rat apolipoprotein A-I promoter activity.
The observation that glucocorticoids increase the abundance of apolipoprotein A-I led us to a search for potential underlying mechanism(s). In this report, we show that the synthetic glucocorticoid, dexamethasone, injected into rats increases serum levels of apoA-I protein, hepatic mRNA and "run-on' transcription of the gene by 3-, 5-, and 2-fold, respectively. Results of transient transfection studies of the rat apoA-I promoter reveal that effects of dexamethasone are mediated by a cis-acting site B (-170 to -145). Dexamethasone treatment of hepatoma cells enhances the DNA binding activity of nuclear factors that bind this site. Unexpectedly, site B does not contain a consensus glucocorticoid receptor recognition motif nor binds to bacterially expressed glucocorticoid receptor. These results indicate that the actions of glucocorticoids on site B involve indirect mechanisms. Site B is comprised of a direct repeat of a nonanucleotide and mutation of either one abolishes the effect of glucocorticoid. Additionally, the transcriptional activity of site B in response to dexamethasone is amplified by a 5' sequence called site S (-186 to -171). Dexamethasone has no effect on site S in the absence of site B. In summary, our data show that dexamethasone increases rat apoA-I gene expression by an indirect mechanism.
Taylor
A H
AH
Department of Medicine, University of Calgary, Alberta, Canada.
Raymond
J
J
Dionne
J M
JM
Romney
J
J
Chan
J
J
Lawless
D E
DE
Wanke
I E
IE
Wong
N C
NC
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D016632:Apolipoprotein A-I; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D004247:DNA