Corticosteroids induce cyclooxygenase 1 expression in cardiomyocytes: role of glucocorticoid receptor and Sp3 transcription factor.
Cyclooxygenase (COX) encodes a rate-limiting enzyme in the biosynthesis of prostanoids. Although COX-1 is constitutively expressed in many tissues, we found that glucocorticoids cause elevated expression of COX-1 gene in cardiomyocytes. Corticosterone (CT) at physiologically relevant doses (0.05-1 microm) induces transcriptional activation of COX-1 gene as shown by nuclear run-on and promoter reporter assays. An antagonist of glucocorticoid receptor (GR), mifepristone, prevented CT from inducing COX-1. COX-1 gene promoter deletion and mutation studies indicate a role of Sp transcription factors in CT-induced COX-1 gene. EMSAs or chromatin immunoprecipitation assays suggest that GR and Sp3 transcription factor bind to the promoter of COX-1 gene. Coimmunoprecipitation assays found an association of GR with Sp3. Silencing Sp3 protein with small interfering RNA suppressed CT-induced COX-1 promoter activation. Our data suggest that activated GR interacts with Sp3 transcription factor in binding to COX-1 promoter to enhance COX-1 gene expression in cardiomyocytes.
Sun
Haipeng
H
Interdisciplinary Graduate Program of Pharmacology and Toxicology, University of Arizona, 1501 North Campbell Avenue, Tucson, Arizona 85724, USA.
Sheveleva
Elena
E
Chen
Qin M
QM
D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D015735:Mifepristone / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; C497123:Sp3 protein, rat; D051705:Sp3 Transcription Factor; D015735:Mifepristone; D004247:DNA; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D003345:Corticosterone