Back to Search
Start Over
Differential Alteration of Heat Shock Protein 90 in Mice Modifies Glucocorticoid Receptor Function and Susceptibility to Trauma
- Source :
- Journal of Neurotrauma. 27:373-381
- Publication Year :
- 2010
- Publisher :
- Mary Ann Liebert Inc, 2010.
-
Abstract
- Heat shock protein 90 (Hsp90), encoded by the murine hsp84 and hsp86 genes in mice, is a pivotal regulator of glucocorticoid receptor (GR) function in the hypothalamus-pituitary-adrenal axis and affords stress protection. To explore the underlying molecular mechanisms of strain susceptibility to traumatic stress, we investigated the alteration by Hsp90 of the function of the glucocorticoid-glucocorticoid receptor (GC-GR) pathway in attenuating stress responses in C57BL/6 and BALB/c mice using the whole-body blast injury (WBBI) model. We found that C57BL/6 mice had a lower WBBI-induced mortality, higher nuclear GR level, and higher glucocorticoid-response element (GRE) binding activity than BALB/c mice. This study is the first report identifying four genetic variations of the murine hsp84 gene: 226AC, 996GC, 1483GC, and 2000GT. These nucleotide changes occur in the functional domains associated with the nuclear/cytosolic translocation of GR, GR-Hsp90 interaction, ATP binding, and self-dimerization of Hsp90, respectively. Further, we used a specific Hsp90 inhibitor, geldanamycin (GA), to assess the role of Hsp90 in the discriminative traumatic response in C57BL/6 mice. Pretreatment with GA reduced nuclear GR levels and GRE binding activity, and enhanced WBBI-induced mortality. These findings suggest that Hsp90 may underlie the strain-selective (C57BL/6 versus BALB/c) susceptibility to WBBI by mediating the nuclear translocation of GRs and GRE binding. Thus, pharmacological manipulation of Hsp90 may represent a therapeutic strategy to modify the function of the GC-GR pathway and traumatic stress response.
- Subjects :
- Male
Hypothalamo-Hypophyseal System
Lactams, Macrocyclic
Blotting, Western
Pituitary-Adrenal System
Chromosomal translocation
Biology
Polymorphism, Single Nucleotide
Mice
chemistry.chemical_compound
Receptors, Glucocorticoid
Glucocorticoid receptor
Blast Injuries
Stress, Physiological
Heat shock protein
Benzoquinones
Animals
Genetic Predisposition to Disease
HSP90 Heat-Shock Proteins
Enzyme Inhibitors
Receptor
Gene
Mice, Inbred BALB C
Reverse Transcriptase Polymerase Chain Reaction
Geldanamycin
Hsp90
Molecular biology
Mice, Inbred C57BL
Cytosol
chemistry
Immunology
biology.protein
Wounds and Injuries
Neurology (clinical)
Subjects
Details
- ISSN :
- 15579042 and 08977151
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Journal of Neurotrauma
- Accession number :
- edsair.doi.dedup.....0df45ed820c8ef6b2ac252e6e9cb59c8