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Modulation of transcription parameters in glucocorticoid receptor-mediated repression. Mol Cell Endocrinol 2008 Nov 25;295(1-2):59-69

Date

06/28/2008

Pubmed ID

18583028

Pubmed Central ID

PMC2662735

DOI

10.1016/j.mce.2008.05.008

Abstract

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.

Author List

Sun Y, Tao YG, Kagan BL, He Y, Simons SS Jr

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Carrier Proteins
Cell Line, Tumor
DNA-Binding Proteins
Dexamethasone
Dose-Response Relationship, Drug
Down-Regulation
Enzyme Inhibitors
Glucocorticoids
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Hydroxamic Acids
Matrix Metalloproteinase 13
Molecular Structure
Nuclear Receptor Co-Repressor 2
Nuclear Receptor Coactivator 1
Nuclear Receptor Coactivator 2
Pregnatrienes
Rats
Receptors, Glucocorticoid
Repressor Proteins
Structure-Activity Relationship
Transcription Factor AP-1
Transcription Factors
Transcription, Genetic
Transfection
Ubiquitin-Conjugating Enzymes
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