Expression and regulation of nuclear receptor coactivators in glucocorticoid action.
Nuclear receptor coactivators are involved in receptor-mediated transcriptional activation of target genes in a hormone-sensitive manner, and the mechanism of their transactivation has been studied in recent years. The glucocorticoid receptor (GR) interacts with several coactivators, including steroid receptor coactivator-1 (SRC-1) family and CREB-binding protein (CBP). Since coactivators function as transcription amplifiers, subtle changes in expression levels of coactivators in certain cells would markedly intensify receptor-mediated transcriptional activity. The regulation of coactivators by glucocorticoid action, however, has not yet been clarified. In this study, we have shown that one of the coactivators interacting with GR, SRC-1, is downregulated by dexamethasone (DEX) both in vivo and in vitro. In experiments on Sprague-Dawley rats in vivo, the downregulation of SRC-1 was observed in heart, stomach, kidney, liver, and cerebrum, and in experiments on two types of kidney-derived cells in vitro, similar downregulation of SRC-1 was demonstrated in both types of cells. DEX-mediated downregulation of SRC-1 mRNA recovered in 4-8 h, while the downregulation of SRC-1 protein lasted for 12 h and its levels returned to the basal level, 24 h after DEX treatment. Other coactivators examined in this study showed no remarkable changes in expression by DEX treatment, implying that ligand-mediated downregulation of SRC-1 has a pivotal role in the physiology of glucocorticoid action.
Kurihara
Isao
I
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan.
Shibata
Hirotaka
H
Suzuki
Toshihiko
T
Ando
Takashi
T
Kobayashi
Sakiko
S
Hayashi
Matsuhiko
M
Saito
Ikuo
I
Saruta
Takao
T
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D051548:Histone Acetyltransferases; D006727:Hormone Antagonists / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D015735:Mifepristone / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D005938:Glucocorticoids; D006727:Hormone Antagonists; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014157:Transcription Factors; D015735:Mifepristone; D003907:Dexamethasone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1