Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation

Kim, Yuli; Sun, Yunguang; Chow, Carson C.; Pommier, ﻿Yves; Simons, S. Stoney

doi:10.1016/j.jsbmb.2006.03.003

Cited by 24 publications

(48 citation statements)

References 89 publications

(187 reference statements)

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“…A recurrent theme with these modulatory proteins is that the V max can be altered independently of EC 50 and partial agonist activity Jr., 1993;Szapary et al, 1996;Szapary et al, 1999;Chen et al, 2000;Zeng et al, 2000;Giannoukos et al, 2001;Song et al, 2001;He et al, 2002;Kaul et al, 2002;Wang et al, 2004a;Wang et al, 2004b;Cho et al, 2005;Kim et al, 2006). This phenomenon is again observed here with GMEB-2 (Table 3A).…”

Section: Discussionsupporting

confidence: 63%

“…In this study, each factor (GME, GMEB-2, Ubc9, and STAMP) that we have previously reported to modulate the EC 50 , partial agonist activity, and V max of GR transactivation Kaul et al, 2000;Zeng et al, 2000;He et al, 2002;Kaul et al, 2002;Cho et al, 2005;Kim et al, 2006;) is found to have some different effect on PRmediate induction or receptor binding under identical transient transfection conditions (Table 3A). Assay conditions under which the GME alters all three properties of GRs have negligible, if any effect, on PRs.…”

Section: Discussionmentioning

confidence: 49%

“…Transfected GR in 1470.2 cells causes squelching of the induction of transfected GREtkLUC reporter (data not shown), indicating that the endogenous levels of GR are already maximal. These are conditions where Ubc9 is expected to significantly decrease the EC 50 and increase both the V max and partial agonist activity Cho et al, 2005;Kim et al, 2006). As listed in Table 2, only the V max of GR induction increases significantly.…”

Section: Modulatory Activity Of Ubc9 With Pr Vs Grmentioning

confidence: 95%

“…Experiments in CV-1 cells have shown that Ubc9 reduces the EC 50 for gene induction to lower concentrations of agonist steroid, and increases the partial agonist activity of antisteroids, only when GR concentrations are high Cho et al, 2005;Kim et al, 2006). The insensitivity to Ubc9 of low concentrations of GR has been ascribed to the presence of an inhibitory sequence in the N-terminal domain of GR.…”

Section: Modulatory Activity Of Ubc9 With Pr Vs Grmentioning

confidence: 99%

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Differential modulation of glucocorticoid and progesterone receptor transactivation

Szapary

Song

et al. 2008

Molecular and Cellular Endocrinology

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The determinants of the different biological activities of progesterone receptors (PRs) vs. glucocorticoid receptors (GRs), which bind to the same DNA sequences, remain poorly understood. The mechanisms by which differential expression of a common target gene can be achieved by PR and GR include unequal agonist steroid concentrations for half maximal induction (EC 50 ) and dissimilar amounts of residual partial agonist activity for antisteroids in addition to the more common changes in total gene induction, or V max . Several factors are known to alter some or all of these three parameters for GR-regulated gene induction and some (i.e., the corepressors NCoR and SMRT) modulate the EC 50 and partial agonist activity for GR and PR induction of the same gene in opposite directions. The current study demonstrates that other factors (GME, GMEB-2, Ubc9, and STAMP) can also differentially interact with PRs and GRs or alter several of the above induction parameters under otherwise identical conditions. These results support the hypothesis that the modulation of EC 50 , partial agonist activity, and V max by a given factor is not limited to one receptor in a specific cell line. Furthermore, the number of factors that unequally modulate PR and GR induction parameters is now greatly expanded, thereby increasing the possible mechanisms for differential gene regulation by PRs vs. GRs.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 49%

Section: Modulatory Activity Of Ubc9 With Pr Vs Grmentioning

confidence: 95%

Section: Modulatory Activity Of Ubc9 With Pr Vs Grmentioning

confidence: 99%

See 2 more Smart Citations

Differential modulation of glucocorticoid and progesterone receptor transactivation

Szapary

Song

et al. 2008

Molecular and Cellular Endocrinology

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“…Possible biological mechanisms are that a cofactor could bind transiently to DNA but affect the DNA state (e.g., methylation, ubiquitination, uncoiling, untwisting, etc. ), facilitate the binding of another cofactor, or alter the mRNA state during translation (6,10,11). Considerable experimental evidence has been advanced in support of transient binding (dubbed "hit and run") of GR to endogenous genes (12,13).…”

Section: If [R] + [Rs] + [Rsd] = R T Can Be Replaced By [R] + [Rs] = mentioning

confidence: 99%

A theoretical framework for gene induction and experimental comparisons

Ong

Blackford

Kagan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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113

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Ligand-mediated gene induction by steroid receptors is a multistep process characterized by a dose-response curve for gene product that follows a first-order Hill equation. This behavior has classically been explained by steroid binding to receptor being the rate-limiting step. However, this predicts a constant potency of gene induction (EC 50 ) for a given receptor-steroid complex, which is challenged by the findings that various cofactors/reagents can alter this parameter in a gene-specific manner. These properties put strong constraints on the mechanisms of gene induction and raise two questions: How can a first-order Hill dose-response curve (FHDC) arise from a multistep reaction sequence, and how do cofactors modify potency? Here we introduce a theoretical framework in which a sequence of steps yields an FHDC for the final product as a function of the initial agonist concentration. An exact determination of all constants is not required to describe the final FHDC. The theory predicts mechanisms for cofactor/reagent effects on gene-induction potency and maximal activity and it assigns a relative order to cofactors in the sequence of steps. The theory is supported by several observations from glucocorticoid receptor-mediated gene induction. It identifies the mechanism and matches the measured dose-response curves for different concentrations of the combination of cofactor Ubc9 and receptor. It also predicts that an FHDC cannot involve the DNA binding of preformed receptor dimers, which is validated experimentally. The theory is general and can be applied to any biochemical reaction that shows an FHDC.dose-response | Michaelis-Menten | gene expression | steroid receptors | glucocorticoids | pharmacology I n ligand-mediated gene induction, the amount of gene expressed depends on the amount of ligand present. Thus, the specific shape and properties of the dose-response curve of gene induction, which is of crucial importance for development, differentiation, and homeostasis in many biological systems, provide a quantitative means for probing the gene-induction process. In many cases, the dose-response curve in gene induction obeys a sigmoidal curve, but not all sigmoidal curves have the same shape. For example, a dose-response curve obeying a first-order Hill equation or function (Hill coefficient equal to 1) goes from 10 to 90% of maximum activity over an 81-fold change in ligand concentration, whereas only a 9-fold change is required in a secondorder Hill function, which thus has a different shape (Fig. S1). (A first-order Hill function is sometimes called a Michaelis-Menten function.) Depending upon the shape of the dose-response curve, the responsiveness of gene induction to the same variation in ligand concentration will differ greatly. In addition to the shape, the position or potency [i.e., concentration required for 50% of maximal response (EC 50 )] and maximum activity (A max ) of the dose-response curve are required to specify the amount of gene expressed for a given amount of ligand. Despite the vital...

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Steroid Hormones

Simons¹

2008

Wiley Encyclopedia of Chemical Biology

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Five categories of steroid hormones exist in humans, including androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins. These hormones affect virtually every tissue and organ in the human body and play major roles in the development, differentiation, and homeostasis of normal individuals. Antisteroids usually possess nonsteroidal structures but still block the actions of the steroid hormones and are important tools in endocrine therapies of pathologic conditions. Therefore, how the body regulates where, when, and how much a response to steroids occurs is of major importance. Here we survey what is known about the genomic responses to steroid hormones, each of which is mediated by a unique intracellular receptor protein that interacts with the cellular DNA to modify the rates of gene transcription. These receptors are members of a much larger superfamily of steroid/nuclear receptors, most of which bind either nonsteroidal ligands or no known ligand. Nongenomic (i.e., pathways without initial involvement of genomic DNA) and secondary responses (i.e., changes that require protein synthesis to alter gene transcription) are additional important effects of steroid hormones but are not discussed here. The emphasis is on the biochemistry of the five classes of steroid hormones, the techniques used to study steroid hormone action, and the basic mechanistic steps by which steroids alter gene expression.

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Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation

Cited by 24 publications

References 89 publications

Differential modulation of glucocorticoid and progesterone receptor transactivation

Differential modulation of glucocorticoid and progesterone receptor transactivation

A theoretical framework for gene induction and experimental comparisons

Steroid Hormones

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