Differential alteration of heat shock protein 90 in mice modifies glucocorticoid receptor function and susceptibility to trauma.
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: 226A>C, 996G>C, 1483G>C, and 2000G>T. 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.
Shen
Hai-Ying
HY
Molecular Biology Center, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, PR China.
Zhao
Yan
Y
Chen
Xing-Yun
XY
Xiong
Ren-Ping
RP
Lu
Jin-Li
JL
Chen
Jiang-Fan
JF
Chen
Li-Yong
LY
Zhou
Yuan-Guo
YG
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001753:Blast Injuries / Q000235:genetics* / Q000378:metabolism*; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000235:genetics; D014947:Wounds and Injuries
D016227:Benzoquinones; D004791:Enzyme Inhibitors; C488983:HSP84 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011965:Receptors, Glucocorticoid; C001277:geldanamycin