Inhibition of glucocorticoid receptor nucleocytoplasmic shuttling by okadaic acid requires intact cytoskeleton

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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
11:07

Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding

Published on: September 21, 2011

M D Galigniana1, P R Housley, D B DeFranco

  • 1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

The Journal of Biological Chemistry
|May 29, 1999
PubMed

Insights

Glucocorticoid receptor (GR) nuclear recycling is blocked by okadaic acid, but this inhibition is overcome by disrupting microtubules. This suggests dephosphorylation is key for GR nuclear entry.

Area of Science:

  • Cell Biology
  • Molecular Endocrinology
  • Signal Transduction

Background:

  • Glucocorticoid receptors (GRs) translocate to the nucleus upon hormone binding.
  • Hormone withdrawal causes GRs to exit the nucleus.
  • Okadaic acid inhibits GR nuclear recycling after hormone withdrawal.

Purpose of the Study:

  • To investigate the role of microtubules and dephosphorylation in GR nuclear recycling.
  • To elucidate the mechanism by which okadaic acid inhibits GR recycling.

Main Methods:

  • Utilized a green fluorescent protein (GFP) GR chimera (GFP-GR).
  • Treated cells with okadaic acid and colcemid (microtubule disruptor).
  • Observed GR localization and interaction with hsp90 under various conditions.

Main Results:

  • Colcemid treatment abrogated okadaic acid inhibition of GR nuclear recycling.
  • In intact cytoskeletons, okadaic acid prevented agonist-dependent dissociation of GR from hsp90.
  • In disrupted cytoskeletons, GR recycled to the nucleus without hsp90 dissociation.

Conclusions:

  • Cytoskeletal integrity is essential for normal GR nuclear recycling.
  • A dephosphorylation event, dependent on an intact cytoskeleton, is required for GR to release hsp90 and enter the nucleus.
  • This suggests a model where dephosphorylation facilitates GR translocation along cytoskeletal tracks.

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