He Zhi-Yong, Wang Wen-Yue, Hu Wei-Yan, Yang Lu, Li Yan, Zhang Wei-Yuan, Yang Ya-Shu, Liu Si-Cheng, Zhang Feng-Lan, Mei Rong, Xing Da, Xiao Zhi-Cheng, Zhang Ming
Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China.
Department of Anatomy and Developmental Biology, Monash University, Melbourne 3800, Australia.
Sci Rep. 2016 Sep 30;6:34558. doi: 10.1038/srep34558.
The PP2C family member Wild-type p53-induced phosphatase 1 (Wip1) critically regulates DNA damage response (DDR) under stressful situations. In the present study, we investigated whether Wip1 expression was involved in the regulation of DDR-induced and depression-related cellular senescence in mouse hippocampus. We found that Wip1 gene knockout (KO) mice showed aberrant elevation of hippocampal cellular senescence and of γ-H2AX activity, which is known as a biomarker of DDR and cellular senescence, indicating that the lack of Wip1-mediated γ-H2AX dephosphorylation facilitates cellular senescence in hippocampus. Administration of the antidepressant fluoxetine had no significant effects on the increased depression-like behaviors, enriched cellular senescence, and aberrantly upregulated hippocampal γ-H2AX activity in Wip1 KO mice. After wildtype C57BL/6 mice were exposed to the procedure of chronic unpredictable mild stress (CUMS), cellular senescence and γ-H2AX activity in hippocampus were also elevated, accompanied by the suppression of Wip1 expression in hippocampus when compared to the control group without CUMS experience. These CUMS-induced symptoms were effectively prevented following fluoxetine administration in wildtype C57BL/6 mice, with the normalization of depression-like behaviors. Our data demonstrate that Wip1-mediated γ-H2AX dephosphorylation may play an important role in the occurrence of depression-related cellular senescence.
蛋白磷酸酶2C家族成员野生型p53诱导磷酸酶1(Wip1)在应激情况下对DNA损伤反应(DDR)起关键调节作用。在本研究中,我们调查了Wip1表达是否参与小鼠海马体中DDR诱导的以及与抑郁相关的细胞衰老的调节。我们发现,Wip1基因敲除(KO)小鼠海马体细胞衰老和γ-H2AX活性异常升高,γ-H2AX是已知的DDR和细胞衰老的生物标志物,这表明缺乏Wip1介导的γ-H2AX去磷酸化会促进海马体中的细胞衰老。给予抗抑郁药氟西汀对Wip1基因敲除小鼠中增加的抑郁样行为、丰富的细胞衰老以及海马体中异常上调的γ-H2AX活性没有显著影响。野生型C57BL/6小鼠在经历慢性不可预测轻度应激(CUMS)后,海马体中的细胞衰老和γ-H2AX活性也升高,与未经历CUMS的对照组相比,海马体中Wip1表达受到抑制。在野生型C57BL/6小鼠中给予氟西汀后,这些CUMS诱导的症状得到有效预防,抑郁样行为恢复正常。我们的数据表明,Wip1介导的γ-H2AX去磷酸化可能在与抑郁相关的细胞衰老的发生中起重要作用。