Genetic Variations of Heat Shock Protein 84 in Mice Mediate Cellular Glucocorticoid Response

Cellular Physiology and Biochemistry

关键词: Heat shock protein 90;    Glucocorticoid receptor;    Heat stress;    Dexamethasone;    Geldanamycin;   

DOI  :  10.1159/000303039

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Heat shock protein 90 (Hsp90), encoded by hsp84 and hsp86 in mice, has been confirmed to modulate glucocorticoid receptor (GR) function; however, the contribution of Hsp90 in glucocorticoid (GC) sensibility/resistance has received less attention. Previously, we found that genetic variations of Hsp84 are related to differences in the in vivo GC-GR responses between BALB/c and C57BL/6 mice suffering from traumatic injury. To evaluate the modulation of Hsp84 polymorphisms on the GC response, we used a cellular heat-stress injury (HSI) model combined with a transgene-plasmid infection approach and assessed HSI-induced cellular damage and GR nuclear translocation, with or without dexamethasone pretreatment. We demonstrated that after HSI, fibroblasts from the C57BL/6 line exhibit higher cellular survival, higher nuclear GR levels and lower lactate dehydrogenase activity compared to those from the BALB/c line. We showed that dexamethasone-rescued HSI-induced damage is accompanied by increasing nuclear GR levels in both lines. Importantly, this protection against HSI was greater in C57BL/6 fibroblasts and was resistant to geldanamycin, a selective inhibitor of Hsp90. Importantly, transfection of the hsp84-transgene from C57BL/6 mice increased the nuclear GR levels and lessened HSI-induced damage in BALB/c fibroblasts. Our data thereby demonstrate that Hsp84 from C57BL/6 mice modulates higher cellular GC-GR responsiveness.

【 授权许可】

CC BY-NC-ND