G protein beta interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus.
Extracellular stimuli that activate cell surface receptors modulate glucocorticoid actions via as yet unclear mechanisms. Here, we report that the guanine nucleotide-binding protein (G protein)-coupled receptor-activated WD-repeat Gbeta interacts with the glucocorticoid receptor (GR), comigrates with it into the nucleus and suppresses GR-induced transactivation of the glucocorticoid-responsive genes. Association of Ggamma with Gbeta is necessary for this action of Gbeta. Both endogenous and enhanced green fluorescent protein (EGFP)-fused Gbeta2 and Ggamma2 proteins were detected in the nucleus at baseline, whereas a fraction of EGFP-Gbeta2 and DsRed2-GR comigrated to the nucleus or the plasma membrane, depending on the exposure of cells to dexamethasone or somatostatin, respectively. Gbeta2 was associated with GR/glucocorticoid response elements (GREs) in vivo and suppressed activation function-2-directed transcriptional activity of the GR. We conclude that the Gbetagamma complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters.
Kino
Tomoshige
T
Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. kinot@mail.nih.gov
Tiulpakov
Anatoly
A
Ichijo
Takamasa
T
Chheng
Ly
L
Kozasa
Tohru
T
Chrousos
George P
GP
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins; D005938:Glucocorticoids / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D013004:Somatostatin / Q000494:pharmacology; D015533:Transcriptional Activation / Q000235:genetics*
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D005938:Glucocorticoids; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D013004:Somatostatin; D003907:Dexamethasone; D019204:GTP-Binding Proteins