Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.
Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.
Cell Death Dis. 2020 May 12;11(5):359. doi: 10.1038/s41419-020-2552-7.
Various stresses, including oxidative stress, impair the proliferative capacity of muscle stem cells leading to declined muscle regeneration related to aging or muscle diseases. ZNF746 (PARIS) is originally identified as a substrate of E3 ligase Parkin and its accumulation is associated with Parkinson's disease. In this study, we investigated the role of PARIS in myoblast function. PARIS is expressed in myoblasts and decreased during differentiation. PARIS overexpression decreased both proliferation and differentiation of myoblasts without inducing cell death, whereas PARIS depletion enhanced myoblast differentiation. Interestingly, high levels of PARIS in myoblasts or fibroblasts induced cellular senescence with alterations in gene expression associated with p53 signaling, inflammation, and response to oxidative stress. PARIS overexpression in myoblasts starkly enhanced oxidative stress and the treatment of an antioxidant Trolox attenuated the impaired proliferation caused by PARIS overexpression. FoxO1 and p53 proteins are elevated in PARIS-overexpressing cells leading to p21 induction and the depletion of FoxO1 or p53 reduced p21 levels induced by PARIS overexpression. Furthermore, both PARIS and FoxO1 were recruited to p21 promoter region and Trolox treatment attenuated FoxO1 recruitment. Taken together, PARIS upregulation causes oxidative stress-related FoxO1 and p53 activation leading to p21 induction and cellular senescence of myoblasts.
各种应激，包括氧化应激，会损害肌肉干细胞的增殖能力，导致与衰老或肌肉疾病相关的肌肉再生能力下降。ZNF746（PARIS）最初被鉴定为 E3 连接酶 Parkin 的底物，其积累与帕金森病有关。在这项研究中，我们研究了 PARIS 在成肌细胞功能中的作用。PARIS 在成肌细胞中表达，并在分化过程中减少。PARIS 过表达既降低了成肌细胞的增殖又降低了分化，而不会诱导细胞死亡，而 PARIS 耗竭则增强了成肌细胞的分化。有趣的是，成肌细胞或成纤维细胞中高水平的 PARIS 诱导细胞衰老，伴随与 p53 信号、炎症和对氧化应激反应相关的基因表达改变。PARIS 在成肌细胞中的过表达显著增强了氧化应激，抗氧化剂 Trolox 的处理减弱了 PARIS 过表达引起的增殖受损。PARIS 过表达细胞中 FoxO1 和 p53 蛋白水平升高，导致 p21 诱导，FoxO1 或 p53 的耗竭降低了 PARIS 过表达诱导的 p21 水平。此外，PARIS 和 FoxO1 都被招募到 p21 启动子区域，Trolox 处理减弱了 FoxO1 的招募。总之，PARIS 的上调导致与氧化应激相关的 FoxO1 和 p53 激活，导致 p21 诱导和成肌细胞的细胞衰老。
