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Kinetically-defined component actions in gene repression.

Chow CC, Finn KK, Storchan GB, Lu X, Sheng X, Simons SS - PLoS Comput. Biol. (2015)

Bottom Line: Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response.The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor.What differs is the position of GR action.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biology Section, NIDDK/LBM, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

No MeSH data available.


Predicted reaction scheme of PMA induction of Luciferase activity from synthetic reporter (AP1LUC) by AP1 that is repressed by steroid-bound receptor (GR).The position of the CLS, and positions of action of TIF2, NU6027, phenanthroline, and GR, as determined by the data of Figs. 3–5, are indicated. A’ and A” represent unknown, post-CLS steps, each of which can lead to Luciferase activity but the efficiency from A” is much less than A’.
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pcbi.1004122.g006: Predicted reaction scheme of PMA induction of Luciferase activity from synthetic reporter (AP1LUC) by AP1 that is repressed by steroid-bound receptor (GR).The position of the CLS, and positions of action of TIF2, NU6027, phenanthroline, and GR, as determined by the data of Figs. 3–5, are indicated. A’ and A” represent unknown, post-CLS steps, each of which can lead to Luciferase activity but the efficiency from A” is much less than A’.

Mentions: Therefore, in this system, the reporter (AP1LUC) and the added cofactors display the same kinetically-defined mechanisms of action, and at the same positions relative to the CLS, in GR-regulated gene repression and gene induction (Fig. 6). The only difference is that the position, but not mechanism, of GR action changes in gene repression from that in gene induction.


Kinetically-defined component actions in gene repression.

Chow CC, Finn KK, Storchan GB, Lu X, Sheng X, Simons SS - PLoS Comput. Biol. (2015)

Predicted reaction scheme of PMA induction of Luciferase activity from synthetic reporter (AP1LUC) by AP1 that is repressed by steroid-bound receptor (GR).The position of the CLS, and positions of action of TIF2, NU6027, phenanthroline, and GR, as determined by the data of Figs. 3–5, are indicated. A’ and A” represent unknown, post-CLS steps, each of which can lead to Luciferase activity but the efficiency from A” is much less than A’.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376387&req=5

pcbi.1004122.g006: Predicted reaction scheme of PMA induction of Luciferase activity from synthetic reporter (AP1LUC) by AP1 that is repressed by steroid-bound receptor (GR).The position of the CLS, and positions of action of TIF2, NU6027, phenanthroline, and GR, as determined by the data of Figs. 3–5, are indicated. A’ and A” represent unknown, post-CLS steps, each of which can lead to Luciferase activity but the efficiency from A” is much less than A’.
Mentions: Therefore, in this system, the reporter (AP1LUC) and the added cofactors display the same kinetically-defined mechanisms of action, and at the same positions relative to the CLS, in GR-regulated gene repression and gene induction (Fig. 6). The only difference is that the position, but not mechanism, of GR action changes in gene repression from that in gene induction.

Bottom Line: Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response.The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor.What differs is the position of GR action.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biology Section, NIDDK/LBM, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

No MeSH data available.