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Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation
Song Her1, Paresh D Patel, Alan F Schatzberg
1Department of Psychiatry, Stanford University Medical Center, Stanford, CA 94305-5485, USA. hersong@stanford.edu
The Journal of Steroid Biochemistry and Molecular Biology
|April 29, 2005
Summary
Glucocorticoid receptor (GR) signaling is impaired in squirrel monkeys due to reduced nuclear translocation. Key amino acids in the ligand-binding domain influence this diminished glucocorticoid receptor function.
Area of Science:
- Molecular Biology
- Endocrinology
- Pharmacology
Background:
- Glucocorticoid resistance is a significant clinical challenge.
- Understanding the molecular basis of impaired glucocorticoid receptor (GR) signaling is crucial for developing effective treatments.
Purpose of the Study:
- To identify the molecular determinants responsible for impaired GR signaling in a model of glucocorticoid resistance.
- To investigate the role of nuclear translocation in diminished GR function.
Main Methods:
- Cloning and tagging of Guyanese squirrel monkey GR (gsmGR) with enhanced green fluorescent protein.
- Transfection of COS1 cells and examination of nuclear translocation.
- Construction and analysis of GR chimeras and truncated mutants.
Main Results:
- Nuclear translocation of gsmGR was diminished compared to human GR (hGR).
- Replacing the gsmGR ligand-binding domain (LBD) with hGR's LBD increased translocation.
- Specific amino acid substitutions (Thr551Ser, Ala616Ser, Ser618Ala) within the LBD of gsmGR restored nuclear translocation.
Conclusions:
- Impaired nuclear translocation is a key factor in the diminished GR signaling observed in this squirrel monkey model.
- Specific amino acids within the LBD are critical for regulating GR nuclear translocation and overall function.