Modulation of transcription parameters in glucocorticoid receptor-mediated repression.
Glucocorticoid receptors (GRs) affect both gene induction and gene repression. The disparities of receptor binding to DNA and increased vs. decreased gene expression have suggested significant mechanistic differences between GR-mediated induction and repression. Numerous transcription factors are known to modulate three parameters of gene induction: the total activity (Vmax) and position of the dose-response curve with glucocorticoids (EC50) and the percent partial agonist activity with antiglucocorticoids. We have examined the effects on GR-mediated repression of five modulators (coactivators TIF2 [GRIP1, SRC-2] and SRC-1, corepressor SMRT, and comodulators STAMP and Ubc9), a glucocorticoid steroid (deacylcortivazol [DAC]) of very different structure, and an inhibitor of histone deacetylation (trichostatin A [TSA]). These factors interact with different domains of GR and thus are sensitive topological probes of GR action. These agents altered the Vmax, EC50, and percent partial agonist activity of endogenous and exogenous repressed genes similarly to that previously observed for GR-regulated gene induction. Collectively, these results suggest that GR-mediated induction and repression share many of the same molecular interactions and that the causes for different levels of gene transcription arise from more distal downstream steps.
Sun
Yunguang
Y
Steroid Hormones Section, NIDDK/CEB, National Institutes of Health, Bethesda, MD, United States.
Tao
Yong-Guang
YG
Kagan
Benjamin L
BL
He
Yuangzheng
Y
Simons
S Stoney
SS
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D015394:Molecular Structure; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C498001:NCOA2 protein, human; C539130:NCOR2 protein, human; C539132:Ncor2 protein, rat; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D011281:Pregnatrienes; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; C517816:TTLL5 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C029415:deacylcortivazol; C012589:trichostatin A; D003907:Dexamethasone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D044763:Ubiquitin-Conjugating Enzymes; D053509:Matrix Metalloproteinase 13; D006655:Histone Deacetylases; D000098843:Ubiquitin-Conjugating Enzyme UBC9