Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, São Paulo, Brazil.
Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Biogerontology. 2020 Oct;21(5):559-575. doi: 10.1007/s10522-020-09869-9. Epub 2020 Mar 18.
Human HSP27 is a small heat shock protein that modulates the ability of cells to respond to heat shock and oxidative stress, and also functions as a chaperone independent of ATP, participating in the proteasomal degradation of proteins. The expression of HSP27 is associated with survival in mammalian cells. In cancer cells, it confers resistance to chemotherapy; in neurons, HSP27 has a positive effect on neuronal viability in models of Alzheimer's and Parkinson's diseases. To better understand the mechanism by which HSP27 expression contributes to cell survival, we expressed human HSP27 in the budding yeast Saccharomyces cerevisiae under control of different mutant TEF promoters, that conferred nine levels of graded basal expression, and showed that replicative lifespan and proteasomal activity increase as well as the resistance to oxidative and thermal stresses. The profile of these phenotypes display a dose-response effect characteristic of hormesis, an adaptive phenomenon that is observed when cells are exposed to increasing amounts of stress or toxic substances. The hormetic response correlates with changes in expression levels of HSP27 and also with its oligomeric states when correlated to survival assays. Our results indicate that fine tuning of HSP27 concentration could be used as a strategy for cancer therapy, and also for improving neuronal survival in neurodegenerative diseases.
人源 HSP27 是一种小分子热休克蛋白，可调节细胞对热休克和氧化应激的反应能力，同时作为一种非 ATP 依赖的伴侣蛋白发挥作用，参与蛋白质的蛋白酶体降解。HSP27 的表达与哺乳动物细胞的存活有关。在癌细胞中，它赋予细胞对化疗的耐药性；在神经元中，HSP27 在阿尔茨海默病和帕金森病模型中对神经元存活具有积极影响。为了更好地理解 HSP27 表达促进细胞存活的机制，我们在芽殖酵母酿酒酵母中，通过控制不同突变 TEF 启动子表达人源 HSP27，这些启动子赋予了 9 个不同水平的基础表达量，结果显示细胞的复制寿命、蛋白酶体活性增加，对氧化应激和热应激的抗性增强。这些表型的特征显示出一种适应现象，即当细胞暴露于越来越多的应激或有毒物质时，会出现一种剂量反应效应。这种适应反应与 HSP27 表达水平的变化以及与存活测定相关的 HSP27 寡聚状态的变化相关。我们的研究结果表明，精细调节 HSP27 浓度可作为癌症治疗的策略，也可用于改善神经退行性疾病中的神经元存活。
