Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, UK; Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Trends Pharmacol Sci. 2015 Jan;36(1):6-14. doi: 10.1016/j.tips.2014.10.011. Epub 2014 Nov 22.
Transcription factors heat shock factor (Hsf)1 and nuclear factor-erythroid 2 p45-related factor (Nrf)2 are critical for adaptation and survival. Each is maintained at low basal levels, but is robustly activated by various stimuli, including cysteine-reactive small molecules (inducers). Although each is regulated by distinct mechanisms, it is emerging that these transcription factors engage in crosstalk by sharing overlapping transcriptional targets, such as heat shock protein (HSP)70, p62, and activating transcription factor (ATF)3, and in certain cases, compensating for each other. Critically, activation of Hsf1 or Nrf2 affects the cellular redox balance by promoting the reduced state. Conversely, deletion of Hsf1 or Nrf2 is associated with oxidative stress and impaired mitochondrial function. Transient activation of Hsf1 and Nrf2 is cytoprotective, but their persistent upregulation may be detrimental, causing cardiomyopathy or accelerating carcinogenesis, and should be considered when designing strategies for disease prevention and treatment.
转录因子热休克因子 (Hsf)1 和核因子-红细胞 2 p45 相关因子 (Nrf)2 对于适应和生存至关重要。每个转录因子的基础水平都很低，但会被各种刺激物（包括含巯基的小分子诱导剂）强烈激活。虽然每个转录因子都受到不同的机制调节，但现在越来越清楚的是，这些转录因子通过共享重叠的转录靶标（如热休克蛋白 (HSP)70、p62 和激活转录因子 (ATF)3）进行串扰，并且在某些情况下，相互补偿。至关重要的是，Hsf1 或 Nrf2 的激活通过促进还原状态来影响细胞的氧化还原平衡。相反，Hsf1 或 Nrf2 的缺失与氧化应激和线粒体功能受损有关。Hsf1 和 Nrf2 的短暂激活具有细胞保护作用，但它们的持续上调可能有害，导致心肌病或加速致癌作用，在设计疾病预防和治疗策略时应予以考虑。
