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Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.
Aging Cell ( IF 7.8 ) Pub Date : 2020-02-16 , DOI: 10.1111/acel.13117
Yonghan He 1 , Wen Li 1 , Dongwen Lv 1 , Xin Zhang 1 , Xuan Zhang 2 , Yuma T Ortiz 1 , Vivekananda Budamagunta 1 , Judith Campisi 3, 4 , Guangrong Zheng 2 , Daohong Zhou 1
Affiliation  

The accumulation of senescent cells (SnCs) is a causal factor of various age‐related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin‐specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro‐apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL‐XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence‐associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy‐induced toxicities and treat age‐related diseases.

中文翻译:

抑制USP7活性部分地通过恢复p53活性来选择性消除衰老细胞。

衰老细胞(SnCs)的积累是各种与年龄有关的疾病以及化学疗法的某些副作用的原因。药理学上消除SnCs(senolysis)有可能被发展为治疗这些疾病和病理状况的新型治疗策略。在这里,我们证明泛素特异性肽酶7(USP7)是一种新型的衰老靶标,因为USP7被抑制剂或USP7的遗传损耗所抑制RNA干扰引起的选择性诱导SnCs凋亡。USP7抑制剂的衰老活性可能部分归因于鼠双分2(MDM2)泛素化和泛素-蛋白酶体系统降解的人类同源性的促进。这种降解增加了p53的水平,从而诱导了促凋亡蛋白PUMA,NOXA和FAS,并抑制了BCL-XL和BAK的相互作用,从而选择性诱导了SnCs的凋亡。此外,我们表明用USP7抑制剂治疗可以有效消除SnCs,并抑制阿霉素诱导的小鼠衰老相关的分泌表型(SASP)。这些发现表明,小分子USP7抑制剂是新型的senolytics,可用于减少化学药品诱导的毒性和治疗与年龄有关的疾病。
更新日期:2020-02-16
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