U.S. Department of Health and Human Services
Stoney Simons Jr
 

 Contact Info

 
Tel: 301-496-6796
Email: stoney.simons@nih.gov
 

 Select Experience

 
  • Postdoctoral FellowUniversity of California, San Francisco1972-1975
  • Ph.D.Harvard University1972
  • B.A.Princeton University1967
 

 Related Links

 

    S. Stoney Simons Jr., Ph.D.

    Senior Investigator, Laboratory of Endocrinology and Receptor BiologySteroid Hormones Section
    Specialties
    • Cell Biology/Cell Signaling
    • Molecular Pharmacology/Toxicology

    Research Summary

    Research Goal

    The purpose of this research is to identify and understand the molecular mechanism of those factors that alter the sensitivity (i.e., the concentration of steroid required for half-maximal activity) and potency (i.e., the maximal activity) of steroid receptor-regulated transcription for different genes in different cells.  With this information, it will be theoretically possible to selectively regulate the expression of numerous genes during development, differentiation, and homeostasis of different organisms. ​

    Current Research

    The major focus of our studies is on the initial events of steroid hormone action at a molecular level.  These events include the equilibrium interactions of cofactors with agonist- and antagonist-bound receptors and the modulation of receptor-mediated gene transcription properties by novel pathways and cofactors.  These studies involve cell-free and whole-cell experiments with wild type and mutant receptors and cofactors.  Some of the techniques used include standard luciferase activities in transfected cells, pulldown and co-immunoprecipitation assays, whole-cell immunofluorescence, ChIP assays, gene knockouts with siRNAs, and mathematical modeling. Most studies utilize the glucocorticoid receptor (GR), progesterone receptor (PR), or androgen receptor (AR), but other receptors are employed as needed.

    The dose-response curves of agonist complexes (or the concentration required for half of the maximal induction; i.e., EC50) and the partial agonist activity of antagonist complexes have been shown to vary, even for the same gene in the same cell.  These variations are of major importance for endocrine therapy and for differential control of gene expression by the single concentration of circulating steroid during development, differentiation, and homeostasis.  These variations are also independent from changes in the total levels of gene activation and thus are proposed to proceed via a different mechanistic pathway.  We have identified numerous components (a novel cis-acting element, coactivators, corepressors, Ubc9, Sur2, and increased concentrations of homologous receptor) that modulate the activities of GRs.  Several of these factors also modulate the activities of PRs, ARs, mineralocorticoid receptors, and estrogen receptors.  Thus, changes in EC50 and partial agonist activity may be a common phenomenon with all classical steroid receptors. Interestingly, the responses of GR and PR to the same factors can be opposite for the same gene in the same cell, thereby providing a clinically relevant mechanism for the different responses of a given cellular gene to a variety of steroid hormones.  More recently, we have developed a new mathematical theory of steroid hormone action that has been used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors, relative to a concentration limiting step and to each other.  The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, were validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells.  The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter.  Thus, new tools are now available to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics.

    Applying our Research

    This research will be of immense benefit to the public by making the currently widespread clinical uses of glucocorticoid steroids (and other steroids) safer, with fewer side effects, and by expanding the applications for which steroids can be used to regulate selectively the expression of specific genes.