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Defect of SIRT1-FoxO3a axis is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated cellular senescence and nematode aging

机译:SIRT1-FoxO3a轴的缺陷与蛋白激酶CK2下调介导的细胞衰老和线虫衰老过程中活性氧的产生有关

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摘要

We investigated whether SIRT1 is associated with reactive oxygen species (ROS) accumulation during CK2 downregulation-mediated senescence. SIRT1 overexpression suppressed ROS accumulation, reduced transcription of FoxO3a target genes, and nuclear export and acetylation of FoxO3a, which were induced by CK2 downregulation in HCT116 and MCF-7 cells. Conversely, overexpression of a dominant-negative mutant SIRT1 (H363Y) counteracted decreased ROS levels, increased transcriptional activity of FoxO3a, and increased nuclear import and decreased acetylation of FoxO3a, which were induced by CK2 upregulation. CK2 downregulation destabilized SIRT1 protein via an ubiquitin-proteasome pathway in human cells, whereas CK2 overexpression reduced ubiquitination of SIRT1. Finally, the SIRT1 activator resveratrol attenuated the accumulation of ROS and lipofuscin as well as lifespan shortening, and reduced expression of the DAF-16 target gene sod-3, which were induced by CK2 downregulation in nematodes. Altogether, this study demonstrates that inactivation of the SIRT1–FoxO3a axis, at least in part, is involved in ROS generation during CK2 downregulation-mediated cellular senescence and nematode aging.
机译:我们调查了SIRT1是否与CK2下调介导的衰老过程中的活性氧(ROS)积累相关。 SIRT1的过表达抑制了HCT116和MCF-7细胞中CK2下调诱导的ROS积累,FoxO3a目标基因的转录减少以及FoxO3a的核输出和乙酰化。相反,显性阴性突变体SIRT1(H363Y)的过表达抵消了CK2上调诱导的ROS水平降低,FoxO3a转录活性增加,核输入增加和FoxO3a乙酰化降低。 CK2下调通过人类细胞中的泛素-蛋白酶体途径使SIRT1蛋白不稳定,而CK2的过表达减少了SIRT1的泛素化。最后,SIRT1激活剂白藜芦醇减弱了线虫中CK2的下调诱导的ROS和脂褐素的积累以及寿命的缩短,并降低了DAF-16靶基因sod-3的表达。总之,这项研究表明,SIRT1–FoxO3a轴的失活至少部分与CK2下调介导的细胞衰老和线虫衰老过程中的ROS产生有关。

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