Hegde R S, Zuo J, Voellmy R, Welch W J
Department of Medicine, University of California, San Francisco 94143, USA.
J Cell Physiol. 1995 Oct;165(1):186-200. doi: 10.1002/jcp.1041650122.
We set out to identify pharmacological means by which to activate the so-called heat shock or stress response and thereby harness the protective effect afforded to the cell by its acquisition of a thermotolerant phenotype. An earlier report by Murakami et al. (1991, Exp. Cell Res., 195: 338-344) described the increased expression of the 70 kDa heat shock proteins in human A431 cells exposed to Herbimycin A (HA), a benzoquinoid ansamycin antibiotic. We show here that treatment of cells with HA results in the increased expression of all of the constitutively expressed stress proteins and confers upon the cells a thermotolerant-like phenotype. Increases in the expression of the stress proteins continued for as long as the cells were exposed to the drug and was independent of the pre-existing levels of the stress proteins. Unlike heat shock or other metabolic stressors, we did not observe any adverse cellular effects following HA exposure. For example, unlike most agents/treatments that elicit the stress response HA-treated cells exhibited no obvious abnormalities with respect to protein maturation, protein insolubility, the integrity of the intermediate filament cytoskeleton, or overall cell viability. In addition, unlike other metabolic stressors, HA treatment did not result in the translocation of hsp 73 into the nucleus/nucleolus. Finally, for at least rodent cells, HA exposure did not result in any obvious activation of the heat shock transcription factor. Based on these findings, we suggest that HA treatment of cells results in a "short-circuiting" of the pathway(s) that normally regulates the expression of the stress proteins. These results are discussed as they pertain to the potential use of HA in animals as a way to harness the protective effects afforded by the stress response.
我们着手确定能够激活所谓热休克或应激反应的药理学方法，从而利用细胞获得耐热表型所赋予的保护作用。村上等人（1991年，《实验细胞研究》，195：338 - 344）早期的一份报告描述了暴露于除草霉素A（HA）（一种苯醌安莎霉素类抗生素）的人A431细胞中70 kDa热休克蛋白表达增加。我们在此表明，用HA处理细胞会导致所有组成性表达的应激蛋白表达增加，并赋予细胞类似耐热的表型。只要细胞暴露于该药物，应激蛋白的表达就会持续增加，且与应激蛋白的预先存在水平无关。与热休克或其他代谢应激源不同，我们在HA暴露后未观察到任何不良细胞效应。例如，与大多数引发应激反应的试剂/处理方法不同，经HA处理的细胞在蛋白质成熟、蛋白质不溶性、中间丝细胞骨架的完整性或总体细胞活力方面没有明显异常。此外，与其他代谢应激源不同，HA处理不会导致hsp 73易位至细胞核/核仁。最后，至少对于啮齿动物细胞，HA暴露不会导致热休克转录因子的任何明显激活。基于这些发现，我们认为用HA处理细胞会导致正常调节应激蛋白表达的途径“短路”。本文将讨论这些结果与HA在动物中潜在用途的相关性，即作为一种利用应激反应所提供保护作用的方法。
