Biphasic JNK-Erk signaling separates the induction and maintenance of cell senescence after DNA damage induced by topoisomerase II inhibition.

IF 9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Systems Pub Date : 2023-07-19 DOI:10.1016/j.cels.2023.06.005
Tatiana S Netterfield, Gerard J Ostheimer, Andrea R Tentner, Brian A Joughin, Alexandra M Dakoyannis, Charvi D Sharma, Peter K Sorger, Kevin A Janes, Douglas A Lauffenburger, Michael B Yaffe
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Abstract

Genotoxic stress in mammalian cells, including those caused by anti-cancer chemotherapy, can induce temporary cell-cycle arrest, DNA damage-induced senescence (DDIS), or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell's environment and/or internal state to control different cell fates. Using single-cell-based signaling measurements combined with tensor partial least square regression (t-PLSR)/principal component analysis (PCA) analysis, we show that JNK and Erk MAPK signaling regulates the initiation of cell senescence through the transcription factor AP-1 at early times after doxorubicin-induced DNA damage and the senescence-associated secretory phenotype (SASP) at late times after damage. These results identify temporally distinct roles for signaling pathways beyond the classic DNA damage response (DDR) that control the cell senescence decision and modulate the tumor microenvironment and reveal fundamental similarities between signaling pathways responsible for oncogene-induced senescence (OIS) and senescence caused by topoisomerase II inhibition. A record of this paper's transparent peer review process is included in the supplemental information.

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双相JNK-Erk信号传导分离拓扑异构酶II抑制诱导的DNA损伤后细胞衰老的诱导和维持。
哺乳动物细胞中的基因毒性应激,包括那些由抗癌化疗引起的应激,可以诱导暂时的细胞周期阻滞、DNA损伤诱导的衰老(DDIS)或凋亡细胞死亡。尽管具有明显的临床重要性,但尚不清楚DNA损伤产生的信号如何与监测细胞环境和/或内部状态的其他细胞信号通路整合在一起,以控制不同的细胞命运。使用基于单细胞的信号测量与张量偏最小二乘回归(t-PLSR)/主成分分析(PCA)分析相结合,我们发现JNK和Erk MAPK信号在阿霉素诱导的DNA损伤后的早期通过转录因子AP-1和损伤后的晚期通过衰老相关分泌表型(SASP)调节细胞衰老的启动。这些结果确定了控制细胞衰老决策和调节肿瘤微环境的经典DNA损伤反应(DDR)之外的信号通路在时间上的不同作用,并揭示了负责癌基因诱导衰老(OIS)和拓扑异构酶II抑制引起的衰老的信号通路之间的基本相似性。本文的透明同行评审过程记录包含在补充信息中。
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来源期刊
Cell Systems
Cell Systems Medicine-Pathology and Forensic Medicine
CiteScore
16.50
自引率
1.10%
发文量
84
审稿时长
42 days
期刊介绍: In 2015, Cell Systems was founded as a platform within Cell Press to showcase innovative research in systems biology. Our primary goal is to investigate complex biological phenomena that cannot be simply explained by basic mathematical principles. While the physical sciences have long successfully tackled such challenges, we have discovered that our most impactful publications often employ quantitative, inference-based methodologies borrowed from the fields of physics, engineering, mathematics, and computer science. We are committed to providing a home for elegant research that addresses fundamental questions in systems biology.
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