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Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation. J Steroid Biochem Mol Biol 2006 Jul;100(1-3):3-17

Date

05/26/2006

Pubmed ID

16723222

DOI

10.1016/j.jsbmb.2006.03.003

Abstract

Varying the concentration of selected factors alters the induction properties of steroid receptors by changing the position of the dose-response curve (or the value for half-maximal induction=EC(50)) and the amount of partial agonist activity of antisteroids. We now describe a rudimentary mathematical model that predicts a simple Michaelis-Menten curve for the multi-step process of steroid-regulated gene induction. This model suggests that steps far downstream from receptor binding to steroid can influence the EC(50) of agonist-complexes and partial agonist activity of antagonist-complexes. We therefore asked whether inhibitors of three possible downstream steps can reverse the effects of increased concentrations of two factors: glucocorticoid receptors (GRs) and Ubc9. The downstream steps (with inhibitors in parentheses) are protein deacetylation (TSA and VPA), DNA unwinding (CPT), and CTD phosphorylation of RNA polymerase II (DRB and H8). None of the inhibitors mimic or prevent the effects of added GRs. However, inhibitors of DNA unwinding and CTD phosphorylation do reverse the effects of Ubc9 with high GR concentrations. These results support our earlier conclusion that different rate-limiting steps operate at low and high GR concentrations versus high GR with Ubc9. The present data also suggest that downstream steps can modulate the EC(50) of GR-mediated induction, thus both supporting the utility of our mathematical model and widening the field of biochemical processes that can modify the EC(50).

Author List

Kim Y, Sun Y, Chow C, Pommier YG, 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

Acetylation
Animals
Cell Line
Cell Line, Transformed
Cell Transformation, Viral
DNA
Dexamethasone
Dichlororibofuranosylbenzimidazole
Dose-Response Relationship, Drug
Enzyme Inhibitors
Glucocorticoids
Hydroxamic Acids
Isoquinolines
Kinetics
Models, Theoretical
Phosphorylation
Plasmids
RNA Polymerase II
Receptors, Glucocorticoid
Trans-Activators
Transcriptional Activation
Transfection
Ubiquitin-Conjugating Enzymes
Valproic Acid
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a