HEAT SHOCK PROTEIN GENE EXPRESSION IN RESPONSE TO STRESS AND AGING

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Heat shock proteins (HSPs), a group of highly conserved proteins induced in response to a variety of cellular stresses, appear to be critical for maintaining cellular homeostasis. We have examined the expression of HSPs in mammalian cells following physiological stresses in vivo and in vitro. In vivo studies: Previously we demonstrated that restraint or immobilization stress elicits the induction of HSP70 mRNA, the major HSP, in the adrenal gland and vasculature of rats. This stress-induced HSP70 expression was found to be attenuated with age. Over the past year we have further characterized this response, and have addressed the mechanism whereby restraint induces this response and the cause for its age-related decline. We have shown using Western analysis that induction of HSP70 mRNA by restraint is followed by an elevation in HSP70 protein. As seen for the mRNA, HSP70 protein expression is reduced in the aged animals. Induction of HSP70 in response to heat and other chemical stressors is mediated transcriptionally through the activation of a specific transcriptional factor, the heat shock factor (HSF), which binds to a specific DNA sequence,the heat shock element (HSE), in the promoter of HSP genes. We have shown that restraint results in the activation of HSF in both the adrenal and vasculature tissues. Tissue extracts from aged animals show reduced levels of HSE-binding activity indicative of either reduced HSF activation or altered binding activity. These findings suggest that the differences in HSP70 expression observed between young and aged rats are likely to be due to differences in an early step in the signal transduction pathway leading to and/or involving transcriptional activation of the HSP70 gene. In vitro studies: Prostaglandins (PG) of the A series are potent inhibitors of cell proliferation. We have shown that PGA1 and PGA2 induce HSP70 mRNA expression in mammalian cells. The effect was shown to be rapid, reversible, dose-dependent and specific for PG capable of arresting growth, and mediated through the activation of HSF. Induction was highly dependent on the growth state of cells, as induction occurred in growing, but not in confluent nongrowing cells. These results support a role for HSP70 in mediating the antiproliferative effects of PGAs.