HEAT SHOCK PROTEIN GENE EXPRESSION IN RESPONSE TO STRESS AND AGING

响应压力和衰老的热休克蛋白基因表达

• 批准号: 3789873
• 负责人: N J HOLBROOK
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3789873
• 关键词: age difference; aging; biological signal transduction; cell cycle; cell growth regulation; gene expression; growth inhibitors; laboratory rat; physiologic stressor; prostaglandins; psychological stressor; restraint; stress proteins; western blottings

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.

热休克蛋白(HSPs)是一组高度保守的诱导蛋白 在对各种细胞压力的反应中，似乎对 维持细胞动态平衡。我们已经检测了热休克蛋白的表达 在体内和体外经历生理应激的哺乳动物细胞中。 活体研究：之前我们证明了克制或 束缚应激诱导HSP70mRNA的诱导，HSP70mRNA是主要的HSP， 在大鼠的肾上腺和血管系统中。这种应激诱导的热休克蛋白70 随着年龄的增长，其表达减弱。在过去的一年里我们 进一步刻画了这一反应的特征，并阐述了机制 克制导致这种反应及其与年龄相关的原因 拒绝。我们已经用Western分析表明，HSP70的诱导 受抑制的信使核糖核酸之后是热休克蛋白70蛋白的升高。如图所示 HSP70蛋白的表达在衰老动物中表达降低。 热应激源和其他化学应激源对HSP70的诱导 通过激活一个特定的基因转录介导的 转录因子，热休克因子(HSF)，与一种 热休克蛋白启动子中的特定DNA序列--热休克元件(HSE) 基因。我们已经证明，限制导致HSF在 包括肾上腺组织和血管组织。老年人的组织提取物 动物表现出HSE结合活性降低的水平，表明 HSF活性降低或结合活性改变。这些发现 提示HSP70在年轻人之间表达的差异 而衰老的大鼠很可能是由于在早期阶段的差异 导致和/或涉及转录的信号转导途径 HSP70基因的激活。 体外研究：A系列前列腺素(PG)有效 细胞增殖的抑制因子。我们已经证明了PGA1和PGA2诱导 热休克蛋白70在哺乳动物细胞中的表达。结果表明，这种影响是 对PG具有快速、可逆、剂量依赖性和特异性抑制作用 生长，并通过激活HSF介导。归纳法是高度 取决于细胞的生长状态，因为诱导发生在生长中， 但不是在融合的不生长的细胞中。这些结果支持了 HSP70在介导PGAs抗增殖作用中的作用