George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Orthopaedics, University of Rochester Medical Center, Rochester, New York 14620, USA.
Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E91-8. doi: 10.1152/ajpendo.00701.2010. Epub 2011 Apr 26.
Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
早期研究表明，TR4 核受体是调节多种生物活性的关键转录因子，包括生殖、小脑发育和代谢。在这里，我们报告说缺乏 TR4（TR4(-/-)）的小鼠表现出基因组不稳定性增加和氧化应激防御缺陷，这与早衰表型有关。在细胞水平上，我们观察到 TR4(-/-) 小鼠胚胎成纤维细胞（MEF）在体外的细胞生长迅速停滞，对氧化应激和 DNA 损伤的抵抗力降低。在 TR4(-/-) MEF 中恢复 TR4 或提供抗氧化剂 N-乙酰-L-半胱氨酸（NAC）可减少 DNA 损伤并减缓细胞生长停滞。聚焦 qPCR 阵列揭示了 TR4(-/-) MEF 中 DNA 损伤反应（DDR）和抗活性氧（ROS）途径的基因谱改变，这进一步支持了这样的假设，即 TR4(-/-) 小鼠的早衰可能源于氧化应激或基因组完整性受损引起的氧化 DNA 损伤。总之，我们的发现确定了 TR4 在介导氧化应激防御与衰老之间相互作用中的新作用。
