Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage
Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage
SUMMARY Genotoxic stress in mammalian cells, including that 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 these different cell fates. Here, using a combination of single cell-based signaling measurements and tensor PLSR/PCA computational approaches, we show that the JNK and Erk MAPK signaling pathways regulate the initiation of senescence through the transcription factor AP-1 at early times after extrinsic DNA damage, and the Senescence Associated Secretory Phenotype, a hallmark of DDIS, at late times after damage. These results identify a time-based separation of function for the same signaling pathways beyond the classic DNA damage response that control the cell senescence decision and modulate the tumor microenvironment following genotoxic stress, and reveal a fundamental similarity between signaling mechanisms responsible for oncogene-induced senescence and senescence caused by extrinsic DNA damaging agents.
Netterfield Tatiana S.、Lauffenburger Douglas A.、Yaffe Michael B.、Ostheimer Gerard J.、Sorger Peter K.、Tentner Andrea R.、Janes Kevin A.
Department of Biological Engineering, Massachusetts Institute of Technology||David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology||Center for Precision Cancer Medicine, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of Technology||David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of Technology||David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology||Center for Precision Cancer Medicine, Massachusetts Institute of Technology||Department of Biology, Massachusetts Institute of Technology||Division of Acute Care Surgery, Trauma, and Surgical Critical Care, and Division of Surgical Oncology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Biological Engineering, Massachusetts Institute of Technology||Department of Biology, Massachusetts Institute of TechnologyLaboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical SchoolDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Biomedical Engineering and Department of Biochemistry & Molecular Genetics, University of Virginia
基础医学细胞生物学分子生物学
Netterfield Tatiana S.,Lauffenburger Douglas A.,Yaffe Michael B.,Ostheimer Gerard J.,Sorger Peter K.,Tentner Andrea R.,Janes Kevin A..Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2022.06.15.496288.点此复制
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