衰老
DNA损伤
细胞生物学
MAPK/ERK通路
生物
细胞周期
信号转导
细胞周期检查点
程序性细胞死亡
细胞凋亡
细胞
细胞信号
细胞生长
遗传学
DNA
作者
Tatiana S. Netterfield,Gerard J. Ostheimer,Andrea R. Tentner,Brian A. Joughin,Alexandra M. Dakoyannis,Chhavi Sharma,Peter K. Sorger,Kevin A. Janes,Douglas A. Lauffenburger,Michael B. Yaffe
出处
期刊:Cell systems
[Elsevier]
日期:2023-07-01
卷期号:14 (7): 582-604.e10
被引量:2
标识
DOI:10.1016/j.cels.2023.06.005
摘要
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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