ArticleProceedings of the National Academy of Sciences of the United States of America2010
A theoretical framework for gene induction and experimental comparisons.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 57 citations in OpenAlex.
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- Dissecting transcriptional amplification by MYC.eLife · 2020Article
- Glucocorticoid and Mineralocorticoid Receptors in the Brain: A Transcriptional Perspective.Journal of the Endocrine Society · 2019Review
- GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life.Frontiers in immunology · 2019Review
- A Model of Glucocorticoid Receptor Interaction With Coregulators Predicts Transcriptional Regulation of Target Genes.Frontiers in pharmacology · 2019Article
- Transcription factor target site search and gene regulation in a background of unspecific binding sites.Journal of theoretical biology · 2018Article
- Structural conditions on complex networks for the Michaelis-Menten input-output response.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- An Approach to Greater Specificity for Glucocorticoids.Frontiers in endocrinology · 2018Review
- Inferring gene regulatory networks from single-cell data: a mechanistic approach.BMC systems biology · 2017Article
- More than meets the dimer: What is the quaternary structure of the glucocorticoid receptor?Transcription · 2017Article
- Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.Pharmacology & therapeutics · 2016Review
- Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction.The Journal of biological chemistry · 2016Article
- Kinetically-defined component actions in gene repression.PLoS computational biology · 2015Article
- Article
- A framework for modelling gene regulation which accommodates non-equilibrium mechanisms.BMC biology · 2014Article
- Research resource: modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay.Molecular endocrinology (Baltimore, Md.) · 2014Article
- A kinase-independent activity of Cdk9 modulates glucocorticoid receptor-mediated gene induction.Biochemistry · 2014Article
- Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges.Molecular endocrinology (Baltimore, Md.) · 2014Review
- A conserved protein motif is required for full modulatory activity of negative elongation factor subunits NELF-A and NELF-B in modifying glucocorticoid receptor-regulated gene induction properties.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.