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Subnuclear Trafficking and Gene Targeting by Steroid Receptors

Authors

  • AKHILESH K. NAGAICH,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • GEETHA V. RAYASAM,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • ELISABETH D. MARTINEZ,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • MATTHIAS BECKER,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • YI QIU,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • THOMAS A. JOHNSON,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • CEM ELBI,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • TERACE M. FLETCHER,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • SAM JOHN,

    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
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  • GORDON L. HAGER

    Corresponding author
    1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA
      Address for correspondence: Gordon L. Hager, Laboratory of Receptor Biology and Gene Expression, Bldg. 41, B602, 41 Library Drive, National Cancer Institute, NIH, Bethesda, MD 20892-5055. Voice: 301-496-9867; fax: 301-496-4951. hagerg@exchange.nih.gov
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    Current address: University of Miami School of Medicine, Dept. of Biochemistry and Molecular Biology, 1011 NW 15th Street, Gautier Bldg., Rm. 210 (R629), Miami, FL 33136.

Address for correspondence: Gordon L. Hager, Laboratory of Receptor Biology and Gene Expression, Bldg. 41, B602, 41 Library Drive, National Cancer Institute, NIH, Bethesda, MD 20892-5055. Voice: 301-496-9867; fax: 301-496-4951. hagerg@exchange.nih.gov

Abstract

Abstract: Through the use of novel imaging techniques, we have observed direct steroid receptor binding to a tandem array of a hormone-responsive promoter in living cells. We found that the glucocorticoid receptor (GR) exchanges rapidly with regulatory elements in the continued presence of ligand. We have also reconstituted a GR-dependent nucleoprotein transition with chromatin assembled on promoter DNA, and we discovered that GR is actively displaced from the chromatin template during the chromatin remodeling process. Using high-intensity UV laser crosslinking, we have observed highly periodic interactions of GR with promoter chromatin. These periodic binding events are dependent on GR-directed hSWI/SNF remodeling of the template and require the presence of ATP. Both the in vitro and in vivo results are consistent with a dynamic model (“hit-and-run”) in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, and is simultaneously lost from the template. We also find that receptor mobility in the nucleoplasm is strongly enhanced by molecular chaperones. These observations indicate that multiple mechanisms are involved in transient receptor interactions with nucleoplasmic targets.

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